CN1187352C - Phenanthrolin-7-one derivatives and their therapeutic use - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising an effective amount of a compound selected from the group consisting of compounds of formula or (Ia) wherein: r₁，R₂，R₃，R₄，R₅And R₇As defined in claim 1. The compounds have interesting cytotoxic properties for use as antitumor agents in therapy.

Description

Phenanthrolin-7-one derivatives and their therapeutic use

The present invention relates to pharmaceutical compositions of polycyclic aromatic compounds, especially as antineoplastic agents.

In 1999, cytotoxic therapy combined with chemical substances (chemotherapy) was used to reduce the size of cancerous tumors, inhibit tumor development or even, in still too few cases, eliminate the risk of tumor mass and metastasis of cancer cells, more recently these Chemicals and others that have been in use for decades have recently been introduced. For example, 5-fluorouracil, (5-FU), known for almost 40 years as the most potent chemical in colon cancer, can be eliminated by either this or that specific topoisomerization when the tumor is no longer sensitive to 5-FU. Enzyme I (irinotecan or topotecan) inhibitor substitution. In general, arsenal, an effective therapy for colon tumors, also has the effect of oxaliplatin, a novel in situ "donor" of 5-FU or a selective inhibitor of thymidylate synthase. This coexistence is not limited to the treatment of colon cancer, since in addition taxane derivatives (paclitaxel, docetaxel) are now widely used in chemotherapy of breast, ovarian and lung cancers. There is still an urgent need for more effective and compatible treatments, thereby increasing the proportion of survivors and prolonging the lifespan of patients, because cases of colon tumors are still increasing, with an estimated 131,000 new cases diagnosed in the United States alone in 1997 , of which 54,000 patients resulted in death (S.L.Parker, T.Tong, S.Bolden et al., CA Cancer J.Clin., 1997). This situation has prompted inventors to focus their attention on polycyclic aromatic compounds identified in the warm sea Ascidian genus, among which have not been studied on a large scale, in order to develop new chemical drugs, selectively synthesized by chemical Design/tuning produces compounds with significant cytotoxic activity at therapeutic levels.

Seas and oceans cover more than 70% of the earth's surface, and grow marine plants and sponges, some of which have been shown to contain complex alkaloids with beneficial pharmacological properties through gradual and systematic pharmacognostic studies. For example, the sponges Cryptotheca crypta and Halichondia okadai have been the subject of intensive study because of the presence of cytarabine or halichondrin B found in their cells. The same is true for tunicates, since aplidine has been isolated from tunicates Aplidium albicans living on balearic islands (Spain).

Alkaloids with a tetrahydroisoquinoline structure have been isolated from the ascidian Ecteinascidiaturbinata. Among them, haiscidin-743 has been the subject of intensive preclinical studies (E.Igbicka et al., NCI-EORTCsymposium, 1998; .130, p.34) and clinical trials (A. Bowman et al., NCI-EORTC symposium, 1998; Abst.452, p.118; M. Villanova-Calero et al., NCI-EORTC symposium, 1998; Abst.453, p.118; M.J.X.Hillebrand et al., NCIEORTC symposium; 1998; Abst.455, p.119; E. Citkovic et al., NCI-EORTC symposium, 1998; Abst.456, p.119). New pentacyclic acridine derivatives have also been the subject of research in medicinal chemistry (D. J. Hagan et al., J. Chem. Soc., Perkin Transf., 1997; 1:2739-2746).

Another marine natural alkaloid, ascididemin, has been extracted from the tunicate Didemnum sp. (J. Kobayashi et al., Tetrahedron Lett., 1988; 29: 1177-80) and from the ascidian Cystodytes dellechiajei (I. Bonnard et al., Anti-cancer Drug Design, 1995; 10:333-46). By FJSchmitz et al. (J.Org.Chem.1991;56:804-8), B.Lindsay et al. (Bioorg.Med.Chem.Lett., 1995;5:739-42) and J.Kobayashi et al. al. (Tetrahedron Lett., 1988; 29: 1177-80) published murine leukemia (P388 or L1210 cell line) model and by I.Bonnard et al. (Anti-cancer Drug Design, 1995; 10: 333- 46) Published human leukemia models demonstrate that Ascididemin has anti-proliferative properties. At the same time, it can also be mentioned that it was isolated from the sea squirt Leptoclinides sp. by SJ Bloor et al. (J. Am. Chem. Soc., 1987; 109: 6134-6) and by F. Bracher et al. 29:2093-95) and then 2-bromoleptoclinidone synthesized by MEJung et al. (Heterocycles, 1994; 39; 2:767-778). 2-bromoleptoclinidone exhibited a cytotoxicity of 0.4 μg/ml ED ₅₀ on leukemia cell models. The nature of cytotoxicity was confirmed by F. Bracher (Pharmazie, 1997; 52:57-60). In vitro experiments were carried out on sixty tumor cell lines in culture, and in vivo experiments were performed on xenogeneic human tumor cell lines implanted in mice. Carried out on transplantation models (colon tumor SW-620 and HTC116, kidney tumor A498 and melanoma LOX IM VI).

Other compounds derived from ascididemin, such as 11-hydroxyascididemin, 11-methoxyascididemin, 11-phenylascididemin, 11-nitrophenylascididemin, 1-nitroascididemin, 3nitroascididemin and neocalliactine, have been published by various groups, such as F.J.Schmitz (J.Org.Chem ., 1991; 56: 804-8) and Y.Kitahara et al. (Heterocycles, 1993; 36: 943-46; Tetrahedron Lett., 1997; 53, 17029-38), G.Gellerman et al. (Tetrahedron Lett. , 1993; 34: 1827-30), S. Nakahara et al., (Heterocycles, 1993; 36: 1139-44) and I. Spector et al. (US-A 5 432 172).

Meridine is another natural alkaloid extracted from the ascidian Amphicarpa merldiana or from the sponge Corticum sp. Meridine was isolated by F.J.Schmifcz et al. (J.Org.Chem., 1991; 56:804-808), and then disclosed by Patent USA 5 182 287 (Gunawardana et al.23 January 1993) in murine leukemia (P388) Antiproliferative properties on the model and its antifungal properties. Its cytotoxic properties on two human cell lines, colon cancer cells (HT-29) and lung cancer cells (A549), were reported by R.E. Longley et al. (J. of Nat. Products, 1993; 56:915-920) .

Mention may also be made among these compounds of cystodamine, a pentacyclic alkaloid isolated from the ascidian Cystodykes dellechiajei by N. Bontemps et al. (Tetrahedron Lett., 1994; 35: 7023-7026), which is effective against human leukemia Lymphoblasts display cytotoxic activity.

The main substances of the present invention are the compounds of general formula I and Ia and the addition salts of these compounds and pharmaceutically acceptable acids:

  和  

and

Formula I Formula Ia

in:

R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are selected from hydrogen, halogen, C ₁ -C ₆ alkyl, hydroxyl, -CHO, -OR ₈ , -COOH, -CN, -CO ₂ R ₈ , - CONHR ₈ , -CONR ₈ R ₉ , -NH ₂ , -NHR ₈ , N(R ₈ ) ₂ , -NH-CH ₂ -CH ₂ -N(CH ₃ ) ₂ , -NH-CH ₂ -CH ₂ -Cl , -NHCOR ₈ , morpholino, nitro, SO ₃ H,

R ₈ and R ₉ are selected from C ₁ -C ₆ alkyl and phenyl(C ₁ -C ₄ )alkyl and Ar is C ₆ -C ₁₄ aryl,

-R ₆ is selected from hydrogen, halogen, C ₁ -C ₆ alkyl or wherein R ₁₀ is selected from halogen or -OH, (C ₁ -C ₆ )alkoxy or -O-CO-(C ₁ -C ₆ ) Alkyl with n between 1 and 6 -(CH ₂ ) _n R ₁₀ group, -CN, -CO ₂ Et or wherein R ₁₁ is selected from C ₁ -C ₆ alkyl and phenyl (C ₁ -C ₄ ) Alkyl -COR ₁₁ group having NR ₁₂ R ₁₃ wherein R ₁₂ and R ₁₃ are independently selected from hydrogen or C ₁ -C ₆ alkyl, phenyl(C ₁ -C ₄ )alkyl or - (CH ₂ ) n R ₁₄ radicals wherein R 14 is selected from halogen or (C ₁ -C ₆ )alkoxy and N(CH ₃ ) ₂ radicals and _n is between 1 _and 6,

-R ₇ is selected from hydrogen, (C ₁ -C ₆ ) alkyl, phenyl (C ₁ -C ₄ ) alkyl, wherein R ₁₅ and R ₁₆ are independently selected from hydrogen, C ₁ -C ₆ alkyl and NR ₁₅ R _{16 of} phenyl ₍ C ₁ -C ₄ )alkyl and ( _{CH 2} ) _n R ₁₇ group.

Particular compounds of formula I and/or 1a are compounds in which the radicals are defined as follows and addition salts of these compounds with pharmaceutically acceptable acids:

R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are selected from hydrogen, halogen, C ₁ -C ₆ alkyl, hydroxyl, -CHO, -OR ₈ , -COOH, -CN, -CO ₂ R ₈ , - CONHR ₈ , -CONR ₈ R ₉ , -NH ₂ , -NHR ₈ , N(R ₈ ) ₂ , -NH-CH ₂ -CH ₂ -N(CH ₃ ) ₂ , -NHCOR ₈ , morpholino, nitrate base, SO ₃ H,

R ₈ and R ₉ are selected from C ₁ -C ₆ alkyl and Ar is C ₆ -C ₁₄ aryl.

More particular substances according to the invention are selected from the compounds of formula (I) and formula (Ia) and the pharmaceutically acceptable acid addition salts of these compounds in which the radicals are defined as follows: wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are selected from hydrogen, halogen, C ₁ -C ₆ alkyl, hydroxyl, -OR ₈ , -NO ₂ , -NH ₂ , -NHR ₈ , -N(R ₈ ) ₂ , -NH-CH ₂ - CH ₂ -N(CH ₃ ) ₂ , -NH-CH ₂ -CH ₂ -Cl, NHCOR ₈ , R ₈ is selected from C ₁ -C ₆ alkyl,

-R ₆ is selected from hydrogen, wherein R ₁₀ is selected from halogen, -O-CO-CH ₃ , -(CH ₂ ) _n R ₁₀ groups of C ₁ -C ₆ alkyl and wherein R ₁₂ and R ₁₃ are independently of each other N(R ₁₂ R ₁₃ ) group selected from hydrogen, C ₁ -C ₆ alkyl, benzyl or wherein R ₁₄ is selected from halogen or (C ₁ -C ₆ )alkoxy and N(CH ₃ ) ₂ groups group and -(CH ₂ ) _n R ₁₄ group with n between 1 and 6,

-R ₇ is selected from hydrogen, (C ₁ -C ₆ ) alkyl, benzyl, wherein R ₁₅ and R ₁₆ are selected from hydrogen, C ₁ -C ₆ alkyl and benzyl N(R ₁₅ R ₁₆ ) groups and (CH ₂ ) _n R ₁₇ groups wherein R ₁₇ is selected from hydrogen, halogen or OH or (C ₁ -C ₆ )alkoxy and n is between 1 and 6.

Preferred compounds are compounds of formulas I and Ia in which at least one of R ₁ , R ₂ , R ₃ , R ₄ and R ₅ is an OR ₈ group.

"Addition salt with a pharmaceutically acceptable acid" means a salt given the biological properties of the free base without adverse effects. These salts are especially salts with inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acids; metal acid salts, such as disodium phosphate and monopotassium sulfate, and organic acids.

Generally, compounds of formula (I) and (Ia) can be obtained by the following methods:

a) According to the endiers-Alder reaction, by the following formula quinoline dione:

and azidodiene of the formula:

where X= _CH3

react to give a mixture of the following compounds

Formula II Formula IIa

b) selectively isolating compounds of formula II and IIa,

_c1 ) Subsequent reaction of compounds of formula II and/or IIa with dimethylformamide dimethyl acetal gives enamines of formula:

and / or

Formula III Formula IIIa

The enamine is then functionalized, introducing R _and /or R _substituents , and cyclized to give compounds I and/or Ia,

or

c ₂ ) while functionalizing and cyclizing, a compound of formula I and/or Ia is obtained,

d) Selective isolation of compounds of formula I and Ia.

In an alternative, compounds of formula I or Ia wherein R _{and R} are hydrogen can be obtained by:

a) make following formula compound:

and azidodiene of the formula:

where X= _CH2 - _CH2 -NHBoc,

react to give a mixture of the following compounds

Formula II Formula IIa

b) selectively isolating compounds of formula II and IIa,

c) cyclization of compounds of formula II and/or IIa to obtain compounds of formula I and/or Ia,

d) selectively isolating a compound of formula I or Ia.

Compounds of formula III and IIIa can be cyclized under heating conditions in the presence of ammonium chloride in a suitable solvent.

Compounds of formula I and Ia are obtained directly from compounds of formula II and IIa when X= _CH2 - _CH2- NHBoc in the presence of sodium bicarbonate in a trifluoroacetic acid medium.

Functionalization to introduce _R6 substituents can be accomplished by derivatizing reactants such as R-COCl, ClCN, _ClCO2Et , _ClCH2OR , _FClO3 or _CH2 =N ⁺ ( _CH3 ) _2I (in acetic acid).

Functionalization to introduce _R7 substituents can be achieved by Mannich reactions using aldehydes of the formula R7 _- CHO.

In this case, cyclization can occur simultaneously in acetic acid in the presence of excess ammonium chloride.

The substituted azidodiene in the examples can be prepared according to the following scheme:

TEMPO = tetramethyl-1-piperidinyloxy, free radical

TBACl = Tetrabutylammonium chloride

FMTP = formylmethylenetriphenylphosphorane

The following examples illustrate the preparation of compounds of formula (I) and (Ia).

Preparation of A-azidodiene (Compound 4)

Synthesis of A-1N-BOC-1-amino-2-hydroxypropane (compound 1)

Add 4.2 g (29.7 mmol) of di-tert-butyl dicarbonate to a solution of 2 ml (27 mmol) of 3-amino-1-propanol in a mixture of 60 ml of dioxane, 30 ml of water and 30 ml of 1N NaOH at 0 °C middle. The reaction mixture was kept stirring at ambient temperature overnight, then acidified to pH 1 using concentrated HCl. After several extractions with ethyl acetate (AcOEt) (3 times in 50 ml), the organic phase was dried over magnesium sulfate and then concentrated on a rotary evaporator to give 4 g of the expected product as a yellow oil.

· Yield: 85%

· ¹ H NMR (CDCl ₃ ): 1.25 (s, 9H); 2.50 (m, 2H); 3.05 (m, 2H); 3.45 (m, 2H); 5.40 (broad s, 1H).

Synthesis of A-2N-BOC-3-aminopropanal (compound 2)

18g (103mmol) compound 1, 1.62g (10.4mmol) TEMPO (tetramethyl-1-piperidinyloxy, free radical), 2.9g (10.45mmol) tetrabutylammonium chloride and 21g (75.5mmol) N _- chlorosuccinimide was suspended in 351 ml sodium bicarbonate/ _K2CO3 . The reaction mixture was stirred vigorously for 2 hours. The organic phase was separated by settling, dried over magnesium sulfate and concentrated on a rotary evaporator to give the expected aldehyde as a pale orange oil.

· Yield: 100%

· ¹ H NMR (CDCl ₃ ): 1.35 (s, 9H); 2.44 (d, 2H, J=6.8Hz); 3.21 (m, 2H); 4.90 (broad s, 1H); 6.04 (dd, 1H, J 8 and 15.6 Hz); 6.74 (td, 1H, J = 6.8 and 15.6 Hz); 9.39 (d, 1H, J = 8 Hz).

Synthesis of A-3N-BOC-5-amino-2-penten-1-al (Compound 3)

11 g (66.7 mmol) of compound 2 and 24.3 g (80 mmol) of formylmethylenetriphenylphosphorane (FMTP) were dissolved in 350 ml of benzene, and the reaction mixture was refluxed for 9 hours. After evaporating the solvent on a rotary evaporator, the residue was first filtered through silica gel [(1/1 chloroform/heptane) then chloroform] to remove triphenylphosphine. Filtration a second time through silica gel (8/2 AcOEt/heptane) afforded 3.88 g of compound 3 as an orange-yellow oil.

Yield: 29%

· ¹ H NMR (CDCl ₃ ): 1.47 (s, 9H); 2.60 (m, 2H) 3.38 (m, 2H); 4.82 (broad s, 1H); 6.18 (dd, 1H); 6.88 (td, 1H) ; 9.55 (d, 1H).

    A-4N-BOC-5-amino-2-pentene-1-aldehyde dimethylhydrazone (compound

Synthesis of compound 4)

3.88 g (19.5 mmol) of compound 3 and 8 drops of acetic acid in 30 ml of ether were added to 1.47 ml (19.5 mmol) of dimethyl trap at 0°C. The reaction mixture was stirred for 10 minutes, the organic phase was separated by settling and washed first with 1N HCl and then with saturated NaCl solution. Drying over _MgSO4 and evaporation on a rotary evaporator afforded 4.4 g hydrazone (compound 4) as an orange-yellow oil.

Yield: 94%

· ¹ H NMR (CDCl ₃ ): 2.30(s, 9H); 2.3(m, 2H); 2.82(m, 2H); 4.52(broad s, 1H); 5.70(td, 1H, J=6.8 and 15.6Hz ); 6.22 (ddd, 1H, J=0.8 and 8.8 and 15.6Hz); 6.96 (d, 1H, J=8.8Hz).

· ¹³ C NMR (CDCl ₃ ): 28.15; 33.05; 39.58; 42.51; 78.77; 130.84; 130.95; 135; 54; 155.68.

B - Preparation of compounds of formula II and IIa

B-1: 4-methylpyrido[2,3-g]quinoline-5,10-dione (intermediate I-1b) and 4-methylpyrido[3,2-g]quinoline-5 , Synthesis of 10-diketone (Intermediate II-1b)

A mixture of 0.5 g (3.14 mmol) of quinoline-5,8-dione, 0.35 g (3.14 mmol) of crotonaldehyde dimethylhydrazone and 0.45 ml (4.76 mmol) of acetic anhydride in 20 ml of chloroform was treated in an ultrasonic bath for 1 Hour. After evaporation of the solvent on a rotary evaporator, the reaction mixture was filtered through silica gel (chloroform), yielding 0.428 g of a mixture of the two isomers I-1a and II-1a in the form of a purple powder. This powder and 1.6 g (18.4 mmol) of manganese dioxide were suspended in 20 ml of chloroform, and the mixture was refluxed for 2 hours. After filtration through celite, the filtrate was concentrated on a rotary evaporator and purified by column flash chromatography on silica gel (98/2 dichloromethane/MeOH) to give:

Intermediate (I-1b): 4-methylpyrido[2,3-g]quinoline-5/10-dione

• 40 mg (yield: 6%) of brown powder.

· Melting point: 220°C.

· ¹ H NMR (CDCl ₃ ): 2.91 (s, 3H); 7.54 (d, 1H, J=4.8Hz); 7.75 (dd, 1H, J=4 and 7.6Hz); 8.67 (dd, 1H, J=4.8Hz); 2 and 7.6 Hz); 8.91 (d, 1H, J=4.8 Hz); 9.12 (dd, 1H, J=2 and 4 Hz).

· ¹³ C NMR (CDCl ₃ ): 22.75; 127.93; 128.04; 129.32; 131.50; 135.50; 148.73; 149.26;

· IR (chloroform): 1689 cm ^-1 .

Intermediate (II-1b): 4-methylpyrido[3,2-g]quinoline-5/10-dione

• 160 mg (yield: 23%) as brown powder.

· Melting point: 270°C.

· ¹ H NMR (CDCl ₃ ): 2.94 (s, 3H); 7.52 (d, 1H, J = 4.8Hz); 7.76 (dd, 1H, J = 4.8 and 8.4Hz); 8.59-(dd, 1H, - J=2 and 8.4Hz); 8.92 (d, 1H, J=4.8Hz); 9.11 (dd, 1H, J=2 and 4.8Hz).

¹³ C NMR (CDCl ₃ ): 22.81; 128.30; 128.39; 130.84; 131.55; 135.52; 147.90; 149.95;

IR (chloroform): 1672; 1700.

B-2: 9-methoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (intermediate I-2b) and 6-methoxy-4-methyl Synthesis of pyrido[3,2-g]quinoline-5,10-dione (intermediate II-2b)

0.5g (2.8mmol) 4-methoxyquinoline-5,8-diketone, 0.32g (2.87mmol) crotonaldehyde dimethyl hydrazone and 0.4ml (4.23mmol) acetic anhydride in 8ml chloroform The mixture was refluxed for 1 hour. After evaporation of the solvent on a rotary evaporator, the reaction mixture was filtered through silica gel (98/2 dichloromethane/methanol), yielding 0.48 g of a mixture of the two isomers I-2a and II-2a in the form of a purple powder. This powder and 2.3 g (26.45 mmol) of manganese dioxide were suspended in 26 ml of chloroform, and the mixture was refluxed for 2 hours. After filtration through celite, the filtrate was concentrated on a rotary evaporator and purified by flash chromatography on a silica gel column (98/2 dichloromethane/MeOH) to give:

Intermediate I-2b: 9-methoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione

· 57 mg (yield: 8%) of red powder.

· ¹ H NMR (CDCl ₃ ): 2.84 (s, 3H); 4.06 (s, 3H); 7.18 (d, 1H, J=6Hz); 7.46 (d, 1H, ss, 1H, J=4.4Hz); 8.87 (d, 1H, J = 6 Hz); 8.87 (d, 1H, J = 4.4 Hz).

Intermediate II-2b: 6-methoxy-4-methylpyrido[3,2-g]quinoline-5,10-dione

• 293 mg (yield: 40%) as an orange powder.

· ¹ H NMR (CDCl ₃ ): 2.80(s, 3H); 4.05(s, 3H); 7.2(d, 1H, J=6Hz); 7.48(d, 1H, J=4.8Hz); 8.85(d, 1H, J=6 Hz); 8.88 (d, 1H, J=4.8 Hz).

^13C NMR ( _CDCl3 ): 21.75; 43.41; 112.74; 119.72; 130.93; 131.04; 148.32; 149.22; 150.26; 151.60;

· IR (chloroform): 1675; 1700 cm ^-1 .

B-3: 9-nitro-4-methylpyrido[2,3-g]quinoline-5,10-dione (intermediate I-5b) and 6-nitro-4-methylpyrido Synthesis of [3,2-g]quinoline-5,10-dione (Intermediate II-5b)

0.8g (3.92mmol) 4-nitroquinoline-5,8-dione, 0.65g (5.8mmol) crotonaldehyde dimethyl hydrazone and 0.55ml (5.8mmol) acetic anhydride in 10.5ml chloroform The mixture was treated in an ultrasonic bath for 30 minutes. After evaporation of the solvent on a rotary evaporator, the reaction mixture was filtered through silica gel (98/2 dichloromethane/methanol), yielding 0.7 g of a mixture of the two isomers I-5a and II-5a as a purple powder. This powder and 2.9 g (33.4 mmol) of manganese dioxide were suspended in 29 ml of chloroform, and the mixture was refluxed for 2 hours. After filtration through celite, the filtrate was concentrated on a rotary evaporator and purified by flash chromatography on a silica gel column (98/2 dichloromethane/MeOH) to give:

Intermediate I-5b: 9-nitro-4-methylpyrido[2,3-g]quinoline-5,10-dione

• 110 mg (yield: 11%) in powder form.

· ¹ H NMR (CDCl ₃ ): 2.98 (s, 3H); 7.19 (d, 1H, J = 5.6Hz); 7.54 (d, 1H, J = 4.8Hz); 8.79 (d, 1H, J = 5.6Hz ); 8.94 (d, 1H, J = 4.8 Hz).

· IR (chloroform): 1703 cm-1.

Intermediate II-5b: 6-nitro-4-methylpyrido[3,2-g]quinoline-5,10-dione

• 165 mg (yield: 16%) as yellow-brown powder.

· ¹ H NMR (CDCl ₃ ): 2.85(s, 3H); 7.6(d, 1H, J=4.8Hz); 7.74(d, 1H, J=4.8Hz); 8.99(d, 1H, J=4.8Hz ); 9.33 (d, 1H, J = 4.8 Hz).

B-4: 9-dimethylamino-4-methylpyrido[2,3-g]quinoline-5,10-dione (intermediate I-3b) and 6-dimethylamino-4-methyl Synthesis of pyrido[3,2-g]quinoline-5,10-dione (intermediate II-3b)

150 mg (0.558 mmol) of nitrated tricyclic compound I-5a or II-5a and 0.4 ml (1.95 mmol) N, N-dimethylformamide diethyl acetal were dissolved in 2.1 ml DMF, and the reaction mixture was Heat at 130°C for 1 hour. After evaporating the solvent with a vacuum pump, 140 mg of intermediate compound II-3a or II-3b were obtained, which were used in the following steps:

Intermediate II-3b: 6-Dimethylamino-4-methylpyrido[3,2-g]quinoline-5,10-dione

· Yield: 94%.

· ¹ H NMR (CDCl ₃ ): 2.77(s, 3H); 3.05(s, 6H); 6.89(d, 1H, J=6Hz); 7.39(d, 1H, J=4.8Hz); 8.42(d, 1H, J=6 Hz); 8.74 (d, 1H, J=4.8 Hz).

B-5: 9-chloro-4-(N-BOC-1-aminoethane)-5,10-dihydropyrido[2,3-g]quinoline-5,10-dione (intermediate I-7b) and 6-chloro-4-(N-BOC-1-aminoethane)-5,10-dihydropyrido[3,2-g]quinoline-5,10-dione (intermediate Synthesis of II-7b)

A mixture of 0.6 g (3.1 mmol) 4-chloroquinoline-5,8-dione, 0.75 g (3.1 mmol) dimethylhydrazone and 0.45 ml (4.76 mmol) acetic anhydride in 8.5 ml chloroform was treated in an ultrasonic bath 30 minutes. After evaporating the solvent on a rotary evaporator, 2.7 g (31.1 mmol) of manganese dioxide and 22 ml of chloroform were added to the reaction mixture, which was refluxed for 2 hours. After filtration through celite, the filtrate was concentrated on a rotary evaporator and purified by column flash chromatography on silica gel (99/1 dichloromethane/methanol) to give:

Intermediate I-7b: 9-chloro 4-(N-BOC-1-aminoethane)-5,10-dihydropyrido[2,3-g]quinoline-5,10-dione:

• 70 mg (yield: 6%) as brown powder.

· ¹ H NMR (CDCl ₃ ): 1.35(s, 9H); 3.45-(m, 4H); 4.86(broad s, 1H); 7.56(d, 1H, J=4.0Hz); 7.74(d, 1H, J=5.2Hz); 8.90(d, 1H, J=5.2Hz); 8.94(d, 1H, J=4Hz)

· ¹³ C NMR (CDCl ₃ ): 28.37; 35.32; 40.30; 79.47; 126.84; 128.04; 130.88; 131.17;

· IR (chloroform): 1695 cm ^-1 .

Intermediate II-7b: 6-chloro 4-(N-BOC-1-aminoethane)-5,10-dihydropyrido[3,2-g]quinoline-5,10-dione:

· 200 mg (yield: 17%) of brown powder.

¹³ C NMR (CDCl ₃ ): 28.24; 34.96; 40.33; 79.47; 128.46; 130.15; 131.06; 131.59; 145.20;

· IR (chloroform): 1705 cm ^-1 .

B-6: 3-methoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (intermediate I-8b) and 3-methoxy-4-methanol Synthesis of pyrido[3,2-g]quinoline-5,10-dione (intermediate II-8b)

A mixture of 1 g (6.28 mmol) of quinoline-5,8-dione and 1.78 g (12.57 mmol) of 2-methoxy-2-butenal dimethylhydrazone in 25 ml of chloroform was stirred at ambient temperature for 5 Hour. After evaporation of the solvent on a rotary evaporator, the reaction mixture was filtered through silica gel (95/2 dichloromethane/methanol), yielding 1.55 g of a mixture of the two isomers I-8a and II-8a as a purple powder. The powder and 1 g (11.5 mmol) of MnO1 were suspended in 30 ml of chloroform, and the mixture was stirred at ambient temperature for 1 hour. After filtration through celite, the filtrate was concentrated on a rotary evaporator and purified by column flash chromatography on silica gel (99/1 dichloromethane/methanol) to give:

Intermediate I-8b: 3-methoxy 4-methylpyrido[2,3-g]quinoline-5,10-dione

• 110 mg (yield: 7%) as brown powder.

· Melting point: >260°C.

· ¹ H NMR (CDCl ₃ ): 2.79(s, 3H); 4.11(s, 3H); 7.72(dd, 1H, J=4.8 and 8, 1Hz); 8.66(s, 1H); 8.67(dd, 1H , J = 8.1 and 1.9 Hz); 9.10 (dd, 1H, J = 4.8 and 1.9 Hz).

· ¹³ C NMR (CDCl ₃ ): 13.03; 56.87; 127.88; 129.50; 129.95; 135.50; 136.64; 139.26; 142.56;

· IR (chloroform): 1684 cm ^-1 .

Intermediate II-8b: 3-methoxy 4-methylpyrido[3,2-g]quinoline-5,10-dione

• 190 mg (yield: 12%) as brown powder.

· Melting point: >260°C.

· ¹ H NMR (CDCl ₃ ): 2.77(s, 3H); 4.12(s, 3H); 7.74(dd, 1H, J=4.6 and 8,0Hz); 8.60(dd, 1H, J=8.0 and 1.6Hz ); 8.68 (s, 1H); 9.12 (dd, 1H, J = 4.6 and 1.6 Hz).

· ¹³ C NMR (CDCl ₃ ): 12.98; 56.93; 127.99; 129.06; 131.27; 135.53; 136.84; 138.81; 143.27;

· IR (chloroform): 1670; 1692 cm ^-1 .

B-7: 3,9-dimethoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (intermediate I-9b) and 3,6-dimethoxy Synthesis of yl-4-methylpyrido[3,2-g]quinoline-5,10-dione (intermediate II-9b)

A solution of 2-methoxyl-2-butenal dimethylhydrazone (1g, 7.1mmol) in 15ml of chloroform was dropped into a solution of 4-methoxyquinoline dione (1.33g, 7mmol) in 30ml of chloroform in solution. Under a nitrogen atmosphere, the reaction mixture was stirred at ambient temperature in the dark for 5 hours. After evaporation of the solvent on a rotary evaporator, the crude product was purified by flash chromatography on silica gel (chloroform, then 98/2 chloroform/MeOH, then 95/5 chloroform/MeOH) to give A first fraction F1 of the desired product and a second fraction containing the desired product. 1 g of manganese dioxide was added to fraction F1 and 30 ml of chloroform. The mixture was stirred for 90 minutes. After filtration through celite, the precipitate was washed with chloroform and then MeOH, and the filtrate was concentrated on a rotary evaporator to obtain fraction F1'. Fractions F1' and F2 were combined and purified by flash chromatography on silica gel (chloroform then 97/3 chloroform/MeOH) to give a mixture of the two expected compounds I9a and II-9b as a brown powder

Intermediate (II-9b): 3,6-dimethoxy 4-methylpyrido[3,2-g]quinoline-5,10-dione

• Yield: 11% (210 mg).

· Melting point: >260°C.

· ¹ H NMR (CDCl ₃ ): 2.68 (s, 3H); 4.09 (s, 3H); 4.10 (s, 3H); 7.18 (d, 1H, J=5.5Hz); 8.60 (s, 1H); 8.88 (d, 1H, J = 5.5 Hz).

· ¹³ C NMR (CDCl ₃ ): 12.85; 56.81; 56.84; 111.14; 121.32; 130.95; 136,43; 137.79;

· IR (chloroform): 1678, 1692 cm ^-1 .

B-8-3-methoxy-4-methyl-9-chloropyrido[2,3-g]quinoline-5,10-dione (intermediate I-10b) and 3-methoxy- Synthesis of 4-Methyl-6-chloropyrido[3,2-g]quinoline-5,10-dione (Intermediate II-10b)

A solution of 2-methoxy-2-butenal dimethylhydrazone (1g, 7.1mmol) in 15ml of chloroform was dropped into a solution of 4-chloroquinoline dione (1.37.1g, 7.1mmol) in 30ml of chloroform middle. Under a nitrogen atmosphere, the reaction mixture was stirred at ambient temperature for 5 hours and 30 minutes in the dark. After evaporation of the solvent on a rotary evaporator, the crude product was purified by flash chromatography on silica gel (chloroform, then 98/2 chloroform/MeOH) to give a first fraction F1 containing non-aromatic product. 1 g of manganese dioxide was added to fraction F1 and 30 ml of chloroform. The mixture was stirred at ambient temperature for 60 minutes. After filtration through celite, the precipitate was washed with chloroform and then MeOH, and the mixture was concentrated on a rotary evaporator. The resulting crude product was purified by flash chromatography on silica gel (97/3 [Iacuna]) to give compounds I-10b and II-10b as yellow powders.

Intermediate II-10b: 3-methoxy 4-methyl-6-chloropyrido[3,2-g]quinoline-5,10-dione

• Yield: 5% (100 mg).

· Melting point: >260°C.

· ¹ H NMR (CDCl ₃ ): 2.68(s, 3H); 4.11(s, 3H); 7.71(d, 1H, J=5.2Hz); 8.64(s, 1H); 8.90(d, 1H, J= 5.2Hz).

· ¹³ C NMR (CDCl ₃ ): 12.96; 56.97; 128.92; 130.72; 130.98; 136.95; 138.12; 141.93; 145.06;

· IR (chloroform): 1696; 1684 cm ^-1 .

B-B-9: 3-methoxy-4-methyl-9-dimethylaminopyrido[2,3-g]quinoline-5,10-dione (intermediate I-11b) and 3-methoxy Synthesis of Oxy-4-methyl-6-dimethylaminopyrido[3,2-g]quinoline-5,10-dione (Intermediate II-11b)

A solution of I-10b or II-10b (90mg, 0.31mmol), dimethylammonium chloride (127mg, 1.56mmol) and NaOH (63mg, 1.56mmol) in a THF/water (4ml/2ml) mixture was refluxed for 1 Hour. After evaporation of the solvent on a rotary evaporator, the crude product obtained was transferred into a 95/5 mixture of dichloromethane/MeOH (50 ml). The organic phase was recovered and dried over magnesium sulfate. After concentration with a rotary evaporator, the resulting crude product was purified by flash chromatography on silica gel (95/5 dichloromethane/MeOH) to afford the expected compound I-11b or II-11b as a yellow powder.

Intermediate II-11b: 3-methoxy 4-methyl-6-dimethylaminopyrido[3,2-g]quinoline-5,10-dione

• Yield: 87% (80 mg).

· Melting point: >260°C.

· ¹ H NMR (CDCl ₃ ): 2.64 (s, 3H); 3.06 (s, 6H); 4.08 (s, 3H); 6.95 (d, 1H, J=5.9Hz); 8.53 (d, 1H,, J = 5.9 Hz); 8.56 (s, 1H).

^13C NMR ( _CDCl3 ): 12.62; 43.40; 56.80; 112.39; 120.50; 132.23; 135.90; 136.08; 141.86;

· IR (chloroform): 1693; 1654 cm ^-1 .

B-B-10: 3,7-dimethoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (intermediate I-12b) and 3,8-dimethoxy Synthesis of yl-4-methylpyrido[3,2-g]quinoline-5,10-dione (intermediate II-12b)

1-2-Methoxyquinoline-5,8-dione

At ambient temperature, a suspension of 5,8-dioxoquinolone (3.1 g, 17.7 mmol), silver carbonate (10.2 g, 37 mmol) and methyl iodide (31 ml, 498 mmol) in 1.2 liters of chloroform was Stir in the dark for 90 hours. The precipitate was removed by filtration, and the filtrate was concentrated with a rotary evaporator. The resulting crude product was purified by filtration over silica gel (chloroform) to afford the expected quinone (2.2 g) as a yellow solid.

• Yield: (66%).

· Melting point: 196°C.

· ¹ H NMR (CDCl ₃ ): 4.14 (s, 3H); 6.95 (d, 1H, J = 10.3Hz); 7.02 (d, 1H, J = 10.3Hz); 7.06 (d, 1H, J = 8.8Hz ); 8.25 (d, 1H, J = 8.8 Hz).

· ¹³ C NMR (CDCl ₃ ): 54.70; 116.68; 124.32; 136.83; 137.54; 138.21; 146.58; 167.14; 183.48; 184.31.

2-3,7-dimethoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (intermediate I-12b) and 3,8-dimethoxy- Synthesis of 4-Methylpyrido[3,2-g]quinoline-5,10-dione (Intermediate II-12b)

A solution of 2-methoxy-2-butyraldehyde dimethylhydrazone (0.75g, 5.3mmol) in 10ml of tetrahydrofuran was dropped into a solution of methoxyquinolinedione (1.0g, 5.3mmol) in 60ml of tetrahydrofuran middle. Under a nitrogen atmosphere, the reaction mixture was stirred at ambient temperature for 40 hours in the dark. After evaporating the solvent on a rotary evaporator, the obtained crude product was dissolved in 80 ml of chloroform and 85% manganese dioxide (5.4 g, 53 mmol) was added. The reaction mixture was stirred for 2 hours, then filtered through celite. After concentration with a rotary evaporator, the resulting crude product was purified by flash chromatography on silica gel (chloroform) to afford compound I-12b or II-12b as a brown powder.

Intermediate (II-12b: 3,8-dimethoxy 4-methylpyrido[3,2-g]quinoline-5,10-dione

• Yield: 8% (120 mg).

· Melting point: >260°C.

· ¹ H NMR (CDCl ₃ ): 2.74(s,); 4.09(s, 3H); 4.20(s, 3H); 7.09(d, 1H, J=8.4Hz); 8.41(d, 1H, J=8.4 Hz); 8.63(s, 1H)

· ¹³ C NMR (CDCl ₃ ):

· IR (chloroform): 1667, 1693 cm ^-1 .

B-11: 8-ethoxycarbonyl-8-(2'-N-BOC-aminoethyl)pyrido[2,3-g]quinoline-5,10-dione (intermediate I-13b) and Synthesis of 7-ethylcarbonyl-6-(2'-N-BOC-aminoethyl)pyrido[3,2-g]quinoline-5,10-dione (intermediate II-13b)

A solution of N-BOC-5-amino-2-pentene-1-aldehyde dimethylhydrazone (1.1g, 4.56mmol) in 15ml of acetonitrile was dropped into 3-ethylquinoline carboxylate-5,8- A solution of diketone (1.05 g, 4.54 mmol) and acetic anhydride (4.6 ml) in 75 ml acetonitrile. Under a nitrogen atmosphere, the reaction mixture was stirred at ambient temperature for 24 hours in the dark. After evaporating the solvent on a rotary evaporator, 5 g of manganese dioxide and 150 ml of chloroform were added to the obtained crude product. The mixture was stirred at ambient temperature for 30 minutes. After filtration through celite, the precipitate was washed with chloroform and then MeOH, and the mixture was concentrated on a rotary evaporator. The resulting crude product was purified first by filtration on silica gel (99/1 then 97/3 dichloromethane/MeOH) and then by flash chromatography on silica gel (99/1) to give compounds I-13b and II as brown powders -13b.

Intermediate II-13b: 7-ethoxycarbonyl-6-(2'-N-BOC aminoethyl)pyrido[3,2-g]quinoline-5,10-dione

• Yield: 3% (60 mg).

· Melting point: 170°C.

· ¹ H NMR (CDCl ₃ ): 1.36 (s, 9H); 1.47 (t, 3H, J = 7.4Hz); 3.52 (m, 4H); 4.51 (q, 2H, J = 7.4Hz); 4.78 (broad s, 1H); 7.57(d, 1H, J=5.2Hz); 8.99(d, 1H, J=5.2); 9.17(d, 1H, J=2.2Hz); 9.64(d, 1H, J=2.2Hz ).

· ¹³ C NMR (CDCL ₃ ): 14.33; 28.40; 35.74; 40.22; 62.62; 79.63; 128.65; 130.33; 130.49; 131.83; 137.30; 149.60; 150.23; 154.23; 155.72; 163.52; 179.9.99; 163.52; 16.9.9.998; 163.52; 16.9.9.99; 163.52; 179.52; 179.52; 179.9.999; 163.52; 179.9.999; 163.52; 179.52;

· IR (chloroform): 3457; 1726; 1705; 1677cm ^-1 .

B-12: 7-Hydroxy-4-(2'N-BOC-aminoethyl)pyrido[2,3-g]quinoline-5,10-dione (Intermediate I-14b) and 8-Hydroxy -Synthesis of 4-(2'N-BOC-aminoethyl)pyrido[3,2-g]quinoline-5,10-dione (intermediate II-14b)

A solution of N-BOC-5-amino-2-penten-1-aldehyde dimethylhydrazone (1.49g, 6.15mmol) in 30ml of acetonitrile was dropped into 5,8-dioxoquinolone (0.98g, 5.59mmol ) and acetic anhydride (5.8ml) in 100ml of acetonitrile. Under a nitrogen atmosphere, the reaction mixture was stirred at ambient temperature for 16 hours in the dark. After evaporating the solvent on a rotary evaporator, 7 g (80.5 mmol) of manganese dioxide and 180 ml of chloroform were added to the crude product obtained. The mixture was stirred at ambient temperature for 30 minutes. After filtration through celite, the precipitate was washed with chloroform and then MeOH, and the mixture was concentrated on a rotary evaporator. The resulting crude product was purified by silica gel filtration (98/2 then 95/5 dichloromethane/MeOH) to give the expected compound I-14b or II-14b as a brown powder.

Intermediate II-14b: 8-ethylhydroxy-4-(2'-N-BOC aminoethyl)pyrido[3,2-g]quinoline-5,10-dione

• Yield: 12% (230 mg).

· Melting point: 252°C.

· ¹ H NMR (CDCl ₃ ): 1.56 (s, 9H); 3.49 (m, 4H); 4.73 (broads, 1H); 6.94 (d, 1H, J=9.6Hz); 7.54 (d, 1H, J= 4.8 Hz); 8.10 (d, 1H, J=9.6 Hz); 8.89 (d, 1H, J=4.8 Hz); 9.66 (broads, 1H).

^13C NMR ( _CDCl3 ): 28.29; 35.53; 40.24; 117.01; 127.87; 128.62; 132.29; 136.18; 138.04;

· IR (chloroform): 3457; 3340; 1693; 1663 cm ^-1 .

B-13: 7-hydroxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (intermediate I-15b) and 8-hydroxy-4-methylpyrido[3 ,2-g] Synthesis of quinoline-5,10-dione (intermediate II-15b)

A solution of 2-crotonaldehyde dimethylhydrazone (0.703g, 6.28mmol) in 20ml of acetonitrile was dropped into 5,8-dioxoquinolone (1g, 5.71mmol) and acetic anhydride (6.2ml) in 220ml of acetonitrile in the solution. Under a nitrogen atmosphere, the reaction mixture was stirred at ambient temperature in the dark for 16 hours and then heated to reflux for 6 hours. After evaporation of the solvent on a rotary evaporator, the crude product was purified by filtration over silica gel (chloroform 2 then 98/2 dichloromethane/MeOH) to give a first fraction containing non-aromatic and expected product. 3 g of manganese dioxide and 75 ml of chloroform were added to the mixture, which was stirred overnight at ambient temperature. After filtration through celite, the precipitate was washed with chloroform and then MeOH, and the mixture was concentrated on a rotary evaporator. The resulting crude product was purified by flash chromatography on silica gel (99/1) to give the expected compounds I-15b and II-15b as beige powders.

Intermediate II-15b: 8-Hydroxy 4-methylpyrrolo[3,2-g]quinoline-5,10-dione

• Yield: 12%.

· Melting point: >260°C.

· ¹ H NMR (CDCl ₃ ): 2.79 (s, 3H); 6.82 (d, 1H, J = 9.5Hz); 7.73 (d, 1H, J = 5.2Hz); 8.05 (d, 1H, J = 9.5Hz ); 8.85 (d, 1H, J = 5.2 Hz); 12.27 (broad s, 1H).

· ¹³ C NMR (d ₆ -DMSO): 21.92; 114.30; 122.66; 127.30; 131.52; 135.94; 148.60; 149.80;

· IR (chloroform): 1684; 1664 cm ^-1 .

B-14: 7-methoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (intermediate I-16b) and 8-methoxy-4-methyl Synthesis of pyrido[3,2-g]quinoline-5,10-dione (intermediate II-16b)

A mixture of compound I-15b or II-15b (70 mg, 0.29 mmol), methyl iodide (1 ml, 15.9 mmol) and Ag ₂ CO ₃ (170 mg, 0.62 mmol) in 100 ml of chloroform was protected from light at ambient temperature Stir for 14 hours, then heat at 56°C for 5 hours. After concentration with a rotary evaporator, the resulting crude product was purified by flash chromatography on silica gel (99.0.5/0.5 dichloromethane/MeOH) to afford the expected compound I-16b or II-16b as a light brown powder.

Intermediate II-16b: 8-methoxy 4-methylpyrido[3,2-g]quinoline-5,10-dione

• Yield: 41% (30 mg).

· Melting point: 128°C.

· ¹ H NMR (CDCl ₃ ): 4.14 (s, 3H); 7.07 (d, 1H, J = 8.8Hz); 7.44 (d, 1H, J = 4.8Hz); 8.37 (d, 1H, J = 8.8Hz ); 8.85 (d, 1H, J = 4.8 Hz).

· ¹³ C NMR (CDCl ₃ ): 54.92; 117.58; 126.24; 128.09; 131.30; 137.73; 147.31; 150.00;

· IR (chloroform): 1765; 1698; 1667; 1603 cm ^-1 .

B-15: 7,9-dichloro-4-methylpyrido[2,3-g]quinoline-5,10-dione (intermediate I-17b) and 6,8-dichloro-4- Synthesis of picoline[3,2-g]quinoline-5,10-dione (intermediate II-17b)

1.2, the synthesis of 4-dichloroquinoline-5,8-diketone Add cerium ammonium nitrate (CAN 21.4g, 39.03mmol) to 2,4-dichloro-5,8-dimethoxyquinoline (2.85 g, 11.04 mmol) in solution in _CH3CN /water mixture (150ml/75ml). The reaction mixture was stirred at ambient temperature for 40 minutes. The acetonitrile was then evaporated, and 50 ml of water and 200 ml of a saturated solution of sodium bicarbonate were added. The aqueous phase was extracted with dichloromethane (5 times 200 ml). After drying over magnesium sulfate, the solvent was evaporated on a rotary evaporator to give the expected compound (1.9 g) as a brown powder.

• Yield: 75%.

· Melting point: 161°C.

· ¹ H NMR (CDCl ₃ ): 7.03 (d, 1H, J=10.6Hz); 7.11 (d, 1H, J=10.6Hz); 7.74 (s, 1H).

· ¹³ C NMR (CDCl ₃ ): 124.43; 131.10; 136.91; 139.52; 146.69; 148.96; 156.16; 180.53; 182.01.

· IR (chloroform): 1687; 1676 cm ^-1 .

2: 7,9-dichloro-4-methylpyrido[2,3-g]quinoline-5,10-dione (intermediate I-17b) and 6,8-dichloro-4-methyl Synthesis of Pyrido[3,2-g]quinoline-5,10-dione (Intermediate II-17b)

A solution of 2-butenal dimethylhydrazone (0.325g, 2.89mmol) in 20ml of acetonitrile was dropped into 2,4-dichloroquinoline-5,8-dione (0.6g, 2.63mmol) and acetic anhydride ( 5ml) in a solution in 100ml acetonitrile. Under a nitrogen atmosphere, the reaction mixture was stirred at ambient temperature for 20 hours in the dark. After evaporation on a rotary evaporator, the crude product obtained was transferred to 140 ml of chloroform. Subsequently 3.65 g of manganese dioxide were added, and the mixture was stirred at ambient temperature for 56 hours. After filtration through celite, the precipitate was washed with chloroform and then MeOH, and the solution was concentrated on a rotary evaporator. The resulting crude product was purified by flash chromatography on silica gel (dichloromethane) to give expected compounds I-17b and II-17b as brown powders.

Intermediate II-17b: 6,8-Dichloro-4-methylpyrido[3,2-g]quinoline-5,10-dione

Yield: 41% (314mg)

· Melting point: 177°C.

· ¹ H NMR (CDCl ₃ ): (s, 3); 7.56 (d, 1H, J=4.8Hz); 7.79 (s, 1H); 8.93 (d, 1H, J=4.8Hz).

· ¹³ C NMR (CDCl ₃ ): 22.41; 125.44; 127.84; 131.13; 131.30; 147.44; 149.81; 150.62;

· IR (chloroform): 1706; 1683 cm ^-1 .

B-16: 7,9-dimethoxy-4-methylpyrido[2,3-g]quinoline-5,10-dione (intermediate I-18b) and 6,8-dimethoxy Synthesis of yl-4-methylpyrido[3,2-g]quinoline-5,10-dione (intermediate II-18b)

A mixture of compound I-17b or compound II-17b (80 mg, 0.27 mmol) and sodium methoxide (300 mg Na in 40 ml methanol, 13.04 mmol) in 40 ml methanol was refluxed for 17 hours. The reaction mixture was concentrated to dryness and 50 ml of water were added. After neutralization with 25% HCl, the solution was extracted with dichloromethane (3 times 50 ml). After drying over magnesium sulfate, the solvent was evaporated on a rotary evaporator to quantitatively obtain the expected compound I-18b or II-18b [Iacuna].

Intermediate II-18b: 6,8-Dimethoxy 4-methylpyrido[3,2-g]quinoline-5,10-dione

· Melting point: 219°C.

· ¹ H NMR (CDCl ₃ ): 2.88 (s, 1H); 4.03 (s, 3H); 4.07 (s, 3H); 6.53 (s, 1H); 7.45 (d, 1H, J=4.8Hz); 8.83 (d, 1H, J = 4.8 Hz).

· ¹³ C NMR (CDCl ₃ ): 22.64; 54.73; 56.80; 97.79; 117.61; 129.55; 131.46; 148.67;

·IR (chloroform) 1701; 1668cm ^-1

Example 1

7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8293) and 7H-pyrido[4,3,2-de][1,7]phenanthrole Lin-7-one (CRL 8294)

Under a nitrogen atmosphere, a mixture of 63 mg (2.81 mmol) of compound I-b and 1.7 ml (9.84 mmol) of dimethylformamide diethyl acetal in 4.5 ml of DMF was left at 120° C. for 1 hour. After evaporating the solvent with a vacuum pump, 3.5 g (65 mmol) of ammonium chloride and 60 ml of absolute ethanol were added. The reaction mixture was refluxed for 30 minutes. After evaporation of ethanol on a rotary evaporator, 50 ml of water are added to the residue and extraction is performed with dichloromethane (3 times 50 ml). After drying the organic phase with magnesium sulfate, the solvent was evaporated on a rotary evaporator to obtain 0.6 g of CRL 8294 as a pale green powder.

7H-Pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8293)

• Yield: 90%.

· Melting point: 240°C.

· ¹ H NMR (CDCl ₃ ): 7.68 (dd, 1H, J=4.4 and 8Hz); 7.87 (d, 1H, J=5.6Hz); 8.02 (d, 1H, J=5.2Hz); 8.77 (dd, 1H, J = 1.6 and 8 Hz); 9.11 (d, 1H, J = 5.2 Hz); 9.16 (dd, 1H, J = 1.6 and 4.4 Hz); 9.19 (d, 1H, J = 5.6 Hz).

· ¹³ C NMR (CDCl ₃ ): 120.95; 124.40; 126.14; 129.32; 136.78; 139.09; 147.45; 148.58; 148.82;

7H-Pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL 8294) Following the procedure described above, starting from intermediate II-Ib, 72 mg of compound CRL was obtained as a yellow powder 8294.

• Yield: 80%.

· ¹ H NMR (CDCl ₃ ): 7.76 (dd, 1H, J=4.4 and 8Hz), 7.80 (d, 1H, J=5.2Hz); 7.99 (d, 1H, J=5.6Hz); 8.93 (d, J = 5.6 Hz); 9.05 (dd, 1H, J = 1.6 and 4.4 Hz); 9.17 (dd, 1H, J = 1.6 and 8 Hz); 9.19 (d, 1H, J = 5.2 Hz).

· ¹³ C NMR (CDCl ₃ ): 119.39; 120.01; 123.85; 128.15; 132.87; 133.80; 138.65; 147.54;

Example 2

8-methoxy-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL8363) and 11-methoxy-7H-pyrido[4,3, 2-de][1,7]phenanthroline-7-one (CRL 8364)

Under a nitrogen atmosphere, a mixture of 74 mg (2.92 mmol) of compound I-2b and 2 ml (11.8 mmol) of dimethylformamide diethyl acetal in 5.2 ml of DMF was left at 120° C. for 1 hour. After evaporating the solvent with a vacuum pump, 4.5 g (83.6 mmol) of ammonium chloride and 67 ml of absolute ethanol were added. The reaction mixture was refluxed for 30 minutes. After evaporation of ethanol on a rotary evaporator, 50 ml of water are added to the residue and extraction is performed with dichloromethane (3 times 50 ml).

After drying the organic phase over magnesium sulfate and evaporating the solvent on a rotary evaporator, the residue was purified by flash chromatography on a silica gel column (98/2 chloroform/MeOH) to give 0.28 g of compound CRL 8363 as an orange powder.

8-Methoxy-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL8363)

• Yield: 37%.

· ¹ H NMR (CDCl ₃ ): 4.20 (s, 3H), 7.13 (d, 1H, J=5.6Hz); 7.82 (d, 1H, J=5.2Hz); 7.94 (d, 1H, J=6Hz) ; 8.92 (d, 1H, J = 5.6Hz); 9.07 (d, 1H, J = 6Hz); 9.13 (d, 1H, J = 5.2Hz); 9.19 (d, 1H, J = 5.2Hz).

· ¹³ C NMR (CDCl ₃ ): 56.77; 109.26; 119.70; 120.47; 123.09; 138.50; 147.85; 148.25; 148.69;

11-Methoxy-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL8364)

Following the procedure described above, starting from 1.14 g of intermediate II-Ib, 0.5 g of compound CRL 8364 was obtained as a yellow powder.

• Yield: 50%.

· ¹ H NMR (CDCl ₃ ): 4.15 (s, 3H); 7.26 (d, 1H, J=6Hz); 7.70 (d, 1H, J=6Hz); 7.96 (d, 1H, J=5.6Hz); 8.85 (d, 1H, J = 6Hz); 8.97 (d, 1H, J = 6Hz); 9.15 (d, 1H, J = 5.6Hz).

· ¹³ C NMR (CDCl ₃ ): 57.05; 111.33; 118.72; 119.61; 122.12; 124.29; 138.56; 146.71;

Example 3

8-(Dimethylamino)-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL 8800) and 11-(dimethylamino)-7H-pyrido [4,3,2-de][1,7]phenanthroline-7-one (CRL 8367)

Under nitrogen atmosphere, the mixture of 80mg (0.3mmol) tricyclic compound I-3b or tricyclic compound II-3b and 0.21ml (1.05mmol) dimethylformamide diethyl acetal in 1.2ml DMF in Place at 120°C for 1 hour. After evaporating the solvent with a vacuum pump, 0.5 g (9.3 mmol) of ammonium chloride and 80 ml of absolute ethanol were added. The reaction mixture was refluxed for 40 minutes. After evaporation of ethanol on a rotary evaporator, 5 ml of water are added to the residue and extraction is performed with dichloromethane (3 times 5 ml). After drying the organic phase with magnesium sulfate, the solvent was evaporated on a rotary evaporator, and two tetracyclic compounds were quantitatively obtained as red powders.

11-(Dimethylamino)-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL 8367)

· ¹ H NMR (CDCl ₃ ): 3.00 (s, 6H), 7.09 (d, 1H, J=5.2Hz) (d, 1H, J=5.6Hz); 7.90 (d, 1H, J=5.2Hz); 8.54 (d, 1H, J = 5.2Hz); 8.89 (d, 1H, J = 5.2Hz); 9.11 (d, 1H, J = 5.6Hz).

Example 4

8-Hydroxy-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL8802) and 11-hydroxy-7H-pyrido[4,3,2-de] [1,7]Phenanthroline-7-one (CRL8388)

50 mg (0.126 mmol) of tricyclic compound I-7b or tricyclic compound II-7b were dissolved in 0.5 ml of TFA, and the reaction mixture was stirred for 24 hours. Trifluoroacetic acid was evaporated on a rotary evaporator, then saturated sodium bicarbonate solution was added until pH 9-10 was reached. The mixture was extracted with dichloromethane (3 times 3 ml). After drying over magnesium sulfate and evaporation of the solvent on a rotary evaporator, 20 mg of the tetracyclic compound was obtained as a yellow powder.

11-Hydroxy-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL8388)

• Yield: 62%.

· Melting point: >260°C.

· ¹ H NMR (CDCl ₃ ): 7.20 (d, 1H, J = 5.6Hz); 7.83 (d, 1H, J = 6Hz); 8.00 (d, 1H, J = 6Hz); 8.72 (d, 1H, J = 6Hz); = 6Hz); 8.76 (d, 1H, J = 6Hz); 9.24 (d, 1H, J = 5.6Hz), 14.65 (s, 1H).

· ¹³ C NMR (d ₆ -DMSO): 116.22; 116.35; 118.61; 120.24; 124.06; 138.09; 143.61; 148.04; 148.99;

Example 5

8-chloro-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL8396) and 11-chloro-7H-pyrido[4,3,2-de] [1,7]Phenanthroline-7-one (CRL8801)

260 mg (0.67 mmol) of tricyclic compound I-7b or tricyclic compound II-7b were dissolved in 2.6 ml of TFA, and the reaction mixture was stirred for 64 hours. The TFA was evaporated on a rotary evaporator, then 200 ml 95/5 dichloromethane/MeOH was added, followed by a saturated solution of sodium bicarbonate until pH 10 was reached. The organic phase is recovered and washed with water. After drying over magnesium sulfate and evaporation of the solvent on a rotary evaporator, 40 mg of the tetracyclic compound was obtained as a brown powder, which was washed with diethyl ether.

8-Chloro-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL 8396)

• Yield: 28%.

· Melting point: >260°C.

· ¹ H NMR (CDCl ₃ ): 7.68 (s, 1H, J = 5.2Hz); 7.89 (d, 1H, J = 5.5Hz); 8.01 (d, 1H, J = 5.5Hz); 8.96 (d, 1H , J=5.2 Hz); 9.14 (d, 1H, J=5.5 Hz) 9.19 (d, 1H, J=5.5 Hz).

· ¹³ C NMR (CDCl ₃ ): 119.87; 120.88; 123.61; 126.31; 129.01; 138.56; 146.87; 147.37;

Example 6

8-methoxy-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL8400) and 4-methoxy-7H-pyrido[4,3, 2-de][1,7]phenanthroline-7-one (CRL8401)

Under nitrogen atmosphere, the mixture of 100mg (0.39mmol) tricyclic compound I-8b or tricyclic compound II-8b and 0.27ml (1.37mmol) dimethylformamide diethyl acetal in 0.7ml DMF was in Place at 120°C for 1 hour. After evaporating the solvent with a vacuum pump, 0.6 g (11.7 mmol) of ammonium chloride and 90 ml of absolute ethanol were added. The reaction mixture was refluxed for 30 minutes. After evaporation of ethanol on a rotary evaporator, 10 ml of water are added to the residue and extraction is performed with dichloromethane (3 times 10 ml). After drying the organic phase over magnesium sulfate, the solvent was evaporated on a rotary evaporator and purified by filtration through silica gel (95/5 dichloromethane/MeOH) to give compounds CRL 8400 and CRL 8401 as brown powders.

4-Methoxy-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL8400)

• Yield: 83% (85 mg).

· Melting point: >260°C.

· ¹ H NMR (CDCl ₃ ): 4.27(s, 3H); 7.65 (dd, 1H, J=4.8 and 8Hz); 8.15(d, 1H, J=6Hz); 8.70(s, 1H); 8.78(dd , 1H, J=8 and 1.9Hz); 9.10 (d, 1H, J=6Hz); 9.13 (dd, 1H, J=1.9 and 4.8Hz).

· ¹³ C NMR (CDCl ₃ ): 56.97; 115.63; 120.81; 125.52; 129.02; 129.16; 130.22; 136.24;

· IR (chloroform): 1674 cm ^-1 .

4-Methoxy-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL8401)

• Yield: 59%.

· Melting point: >260°C.

· ¹ H NMR (CDCl ₃ ): 4.27 (s, 3H); 7.74 (dd, 1H, J = 4.4 and 8.1 Hz); 8.08 (d, 1H, J = 5.6 Hz); 8.72 (s, 1H); 8.93 (d, 1H, J=5.6Hz); 9.05 (dd, 1H, J=1.9 and 4.4Hz); 9.19 (dd, 1H, J=1.9 and 8.1Hz).

· ¹³ C NMR (d ₆ -DMSO): 57.03; 115.16; 119.70; 127.69; 129.48; 130.15; 132.86; 133.74; 140.82;

· IR (chloroform): 1679 cm ^-1 .

Example 7

4,8-dimethoxy-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL 8803) and 4,11-dimethoxy-7H- Pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL 8440)

A solution of compound I-9b or compound II-9b (100mg, 0.35mmol) and N,N-dimethylformamide diethyl acetal (0.24ml, 1.23mmol) in 1ml DMF was placed at 120°C for 90 minute. The reaction mixture was concentrated under high vacuum to remove DMF, and the residue was diluted in 100 ml anhydrous EtOH.

After adding 0.6 g of ammonium chloride, the mixture was refluxed for 30 minutes. After concentration on a rotary evaporator, 30 ml of water were added and the mixture was extracted with chloroform (3 times 75 ml). The organic phase was dried over magnesium sulfate and concentrated. The resulting crude product was purified by flash chromatography on silica gel (95/5 chloroform/MeOH) to afford the compound as a yellow powder. 4,11-Dimethoxy-7H pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL 8440)

• Yield: 26% (27 mg).

· Melting point: >260°C.

· ¹ H NMR (d ₆ -DMSO): 4.08(s, 3H); 4.26(s, 3H); 7.54(d, 1H, J=5.9Hz); 7.98(d, 1H, 5.9Hz); 8.77(d , 1H, J=5.9Hz); 8.83(s, 1H); 8.94(d, 1H, J=5.9Hz).

· ¹³ C NMR (CDCl ₃ ): 57.41; 58.07; 112.43; 113.75; 119.84; 122.13; 129.60; 130.54; 140.17;

· IR (chloroform): 1682; 1608; 1572 cm ^-1 .

MS: m/z 293(34); 292(42); 220(19); 192(30:165(22).

Example 8

4-methoxy-8-dimethylamino-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL 8804) and 4-methoxy-11 di Methylamino-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL 8441)

The solution of compound I-11b or compound II-11b (80mg, 0.27mmol) and N,N-dimethylformamide diethyl acetal (0.18ml, 0.94mmol) in 2ml DMF was placed at 120°C for 3 small clock. The reaction mixture was concentrated under high vacuum to remove DMF, and the residue was diluted in 90 ml anhydrous EtOH. After adding 0.4 g of ammonium chloride, the mixture was refluxed for 30 minutes. 30 ml of water were added and the solution was extracted with dichloromethane (3 times 50 ml). The organic phase was dried over magnesium sulfate and concentrated.

The resulting crude product was purified by flash chromatography on silica gel (95/5 dichloromethane/MeOH) to afford the tetracyclic compound as a reddish-brown powder.

4-Methoxy-11-dimethylamino-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL 8441)

• Yield: 40% (33 mg).

· Melting point: Decompose.

· ¹ H NMR (CDCl ₃ ): 3.02(s, 6H); 4.23(s, 3H); 7.08(d, 1H, J=5.9Hz); 7.87(d, 1H, J=5.5Hz); 8.54(d , 1H, J=5.9Hz); 8.65(s, 1H); 8.90(d, 1H, J=5.5Hz).

^13C NMR ( _CDCl3 ): 44.28; 56.94; 112.14; 113.63; 119.38; 119.73; 129.31; 129.99; 140.20;

· IR (chloroform): 1682 cm ^-1 .

MS: m/z 306(52); 305(32); 291(100); 290(66); 276(24); 248(9); 220(13); 193(21).

Example 9

4,10-dimethoxy-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL 8805) and 4,9-dimethoxy-7H- Pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL 8479)

A solution of compound I-12b or compound II-12b (100mg, 0.35mmol) and N,N-dimethylformamide diethyl acetal (0.24ml, 1.23mmol) in 1ml DMF was placed at 120°C for 1 Hour. The reaction mixture was concentrated under high vacuum to remove DMF, and the residue was diluted in 100 ml anhydrous EtOH.

After adding 0.54 g of ammonium chloride, the mixture was refluxed for 30 minutes. After concentration with a rotary evaporator, 20 ml of water were added and the solution was extracted with chloroform (3 times 30 ml). The organic phase was dried over magnesium sulfate and concentrated. The resulting crude product was purified by flash chromatography on silica gel (chloroform) to afford the tetracyclic compound as a green powder.

4,9-Dimethoxy-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL8479)

• Yield: 36% (37 mg).

· Melting point: >260°C.

· ¹ H NMR (d ₆ -DMSO): 4.21(s, 3H); 4.24(s, 3H); 7.16(d, 1H, J=8.8Hz); 7.98(d, 1H, 5.6Hz); 8.69(s , 1H); 8.85 (d, 1H, J = 5.6 Hz); 9.00 (d, 1H, J = 8.8 Hz).

· ¹³ C NMR (d ₆ -DMSO): 54.44; 56.92; 114.04; 117.17; 118.86; 127.74; 129.43; 129.99; 136.29;

· IR (chloroform): 1679 cm ^-1 .

MS: m/z 293(44); 248(100); 220(12).

Example 10

9-ethoxycarbonyl-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL 8805) and 10-ethoxycarbonyl-7H-pyrido[4,3 , 2-de][1,7]phenanthroline-7-one (CRL 8482)

A solution of compound I-13b or compound II-13b (30 mg, 0.07 mmol) and trifluoroacetic acid (0.27 ml, 3.5 mmol) in 15 ml of dichloromethane was stirred for 64 hours. After concentration with a rotary evaporator, 10 ml of saturated sodium bicarbonate solution were added to basify and the solution was extracted with chloroform (2 times 30 ml). The organic phase was dried over magnesium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by silica gel filtration to afford the tetracyclic compound as a yellow powder.

10-Ethoxycarbonyl-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL 8482)

• Yield: 53% (11.3 mg).

· Melting point: 246°C.

· ¹ H NMR (CDCl ₃ ): 1.49 (t, 3H, J = 7.3Hz); 4.53 (q, 2H, J = 7.3Hz); 7.85 (d, 1H J = 5.9Hz); 8.03 (d, 1H, J=5.5Hz); 8.98(d, 1H, J=5.9Hz); 9.22(d, 1H, J=5.5Hz); 9.56(d, 1H, J=1.9Hz); 9.73(d, 1H, J= 1.9Hz).

^13C NMR ( _CDCl3 ): 14.32; 62.29; 119.61; 120.39; 124.04; 129.94; 132.60; 135.46; 138.77; 147.78; 149.17; 149.46; 153.23;

· IR (chloroform): 1726; 1694 cm ^-1 .

MS: m/z 305(92); 260(7); 232(93); 204(25).

Example 11

10-Hydroxy-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL8809) and 9-hydroxy-7H-pyrido[4,3,2-de] [1,7]Phenanthroline-7-one (CRL8483)

A solution of compound 1-14b or compound 11-14b (tricyclic compound 56) (50 mg, 0.135 mmol) and trifluoroacetic acid (0.54 ml, 7 mmol) in 30 ml of dichloromethane was stirred for 48 hours. After concentration with a rotary evaporator, the reaction mixture was basified by adding 13 ml of saturated sodium bicarbonate solution and extracted with dichloromethane (7 times 30 ml). The organic phase was dried over magnesium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by flash chromatography on silica gel (97/2 dichloromethane/MeOH) to afford the tetracyclic compound as an orange powder.

9-Hydroxy-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL8483)

• Yield: 50% (16.8 mg).

· Melting point: >260°C.

· ¹ H NMR (CDCl ₃ ): 7.06 (d, 1H, J = 9.5Hz); 7.72 (d, 1H, J = 5.9Hz); 8.02 (d, 1H, J = 5.2Hz); 8.70 (d, 1H , J=9.5 Hz); 8.87 (d, 1H, J=5.9 Hz); 9.19 (d, 1H, J=5.5 Hz).

· IR (chloroform): 1690; 1667; 1602 cm ^-1 .

MS: m/z 249 (100); 221 (77.6); 193 (99.2).

Example 12

10-methoxy-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL 8810) and 9-methoxy-7H-pyrido[4,3 , 2-de][1,7]phenanthroline-7-one (CRL 8484)

A solution of compound 1-16b or compound 11-16b (200 mg, 0.786 mmol) and N,N-dimethylformamide diethyl acetal (0.47 ml, 2.73 mmol) in 3.2 ml DMF was refluxed for 2 hours. The reaction mixture was concentrated under high vacuum to remove DMF, and the residue was diluted in 200 ml anhydrous EtOH. After adding 1.4 g of ammonium chloride, the solution was refluxed for 30 minutes. After concentration on a rotary evaporator, 50 ml of water were added and the solution was extracted with dichloromethane (5 times 40 ml). The organic phase was dried over magnesium sulfate and concentrated. The resulting crude product was purified by flash chromatography on silica gel (99/1 dichloromethane/MeOH) to afford the tetracyclic compound as a brown powder.

9-Methoxy-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL8484)

• Yield: 10% (20 mg).

· Melting point: >260°C.

· ¹ H NMR (CDCl ₃ ): 4.14 (s, 3H); 7.11 (d, 1H, J = 8.8Hz); 7.63 (d, 1H, J = 5.5Hz); 7.87 (d, 1H, J = 5.5Hz ); 8.77 (d, 1H, J = 5.5Hz); 8.91 (d, 1H, J = 8.8Hz); 9.09 (d, 1H, J = 5.5Hz).

^13C NMR ( _CDCl3 ): 53.41; 117.66; 118.54; 118.93; 123.70; 127.73; 136.29; 138.52;

· IR (chloroform): 1686 cm ^-1 .

MS: m/z 263 (8.2); 233 (25.1); 1204 (35.4).

Example 13

8,10-dimethoxy-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL 8811) and 9,11-dimethoxy-7H- Pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL 8485)

A solution of compound I-18b or compound II-18b (105mg, 0.37mmol) and N,N-dimethylformamide diethyl acetal (0.22ml, 1.29mmol) in 1.5ml DMF was refluxed for 30 minutes. The reaction mixture was concentrated under high vacuum to remove DMF, and the residue was diluted in 95 ml anhydrous EtOH. After adding 0.7 g of ammonium chloride, the solution was refluxed for 30 minutes. After concentrating with a rotary evaporator, 50 ml of water were added. The solution was extracted with dichloromethane (5 times 40 ml). The organic phase was dried over magnesium sulfate and concentrated. The resulting crude product was purified by flash chromatography on silica gel (99/1 dichloromethane/MeOH) to afford the tetracyclic compound as a yellow-orange powder.

9,11-Dimethoxy-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL 8485)

• Yield: 9% (10 mg).

· Melting point > 260°C.

· ¹ H NMR (CDCl ₃ ): 4.12 (s, 3H); 4.18 (s, 3H); 6.65 (s, 1H); 7.64 (d, 1H; = 5.5Hz); 7.92 (d, 1H, J = 5.5 Hz); 8.93 (d, 1H, J = 5.5 Hz); 9.14 (d, 1H, J = 5.5 Hz).

· ¹³ C NMR (CDCl ₃ ): 54.39; 57.02; 98.26; 117.89; 118.64; 118.86; 124.16; 138.50;

· IR (chloroform): 1688 cm ^-1 .

MS: m/z 293(15); 292(28); 233(24); 204(13); 165(10).

Example 14

8-Dimethylamino-10-chloro-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL 8812) and 9-chloro-11-dimethylamino- 7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL 8485)

A solution of compound I-17b or compound II-17b (110 mg, 0.375 mmol) and N,N-dimethylformamide diethyl acetal (0.23 ml, 1.31 mmol) in 1.1 ml DMF was refluxed for 30 minutes. The reaction mixture was concentrated under high vacuum to remove DMF, and the residue was diluted in 95 ml anhydrous EtOH. After adding 0.7 g of ammonium chloride, the mixture was refluxed for 30 minutes and then concentrated on a rotary evaporator. 50 ml of water were added and the solution was extracted with dichloromethane (5 times 40 ml). The organic phase was dried over magnesium sulfate and concentrated. The resulting crude product was purified by flash chromatography on silica gel (99/1 dichloromethane/MeOH) to afford the tetracyclic compound as a purple-red powder.

9-Chloro-11-dimethylamino-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL 8486)

• Yield: 3% (3.3 mg).

· Melting point: 246°C.

· ¹ H NMR (CDCl ₃ ): 3.04 (s, 6H); 7.11 (s, 1H); 7.61 (d, 1H, J = 5.5Hz); 7.92 (d, 1H, J = 5.5Hz); 8.90 (d , 1H, J=5.5Hz); 9.14 (d, 1H, J=5.5Hz).

· ¹³ C NMR (CDCl ₃ ): 44.39; 113.57; 117.60; 119.00; 119.37; 123.99; 138.50; 146.51; 146.77;

· IR (chloroform): 1698 cm ^-1 .

MS: m/z 311(19); 309(11); 296(89); 294(100); 269(4); 267(1); 204(66).

Example 15

4-Hydroxy-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one dihydroiodide (CRL 8813) and 4-hydroxy-7H-pyrido[4, 3,2-de][1,7]phenanthrolin-7-one dihydroiodide (CRL 8487)

Hydroiodic acid (57%, in water: 10 ml, 44.6 mmol) was added to a suspension of compound CRL 8400 or compound CRL 8401 (50 mg, 0.19 mmol) in acetic acid (4 ml). The mixture was heated at 100°C for 21 hours.

After cooling and filtering, the desired compound dihydroiodide was isolated as a purple powder.

4-Hydroxy-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one dihydroiodide (CRL 8487)

• Yield: 85% (82 mg).

· Melting point: >260°C.

· ¹ H NMR (d ₆ -DMSO): 6.75 (d, 1H, J=5.8Hz); 7.42 (broads, 1H); 7.63 (dd, 1H, J=8.4 and 4.4Hz); 8.20 (d, 1H, J = 5.8 Hz); 9.07 (m, 2H).

· IR (chloroform): 3037; 1647; 1635; 1617; 1604cm ^-1 .

Example 16

4-chloro-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL8806) and 4-chloro-7H-pyrido[4,3,2-de] [1,7]Phenanthroline-7-one (CRL8480)

A solution of compound CRL 8813 or compound CRL 8487 (45 mg, 0.14 mmol) in _POCl3 (3.5 ml) was refluxed for 2 hours. After evaporation on a rotary evaporator, the mixture was basified to pH 8 with 1 N sodium bicarbonate solution (10 ml) and extracted with a 5% MeOH/chloroform mixture (2 x 20 ml). The organic phase was dried over magnesium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by flash chromatography (99/1 dichloromethane/MeOH) to afford the tetracyclic compound as a brown powder.

4-Chloro-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL 8480)

• Yield: 4% (2 mg).

· Melting point: >260°C.

· ¹ H NMR (CDCl ₃ ): 7.78 (dd, 1H, J = 4.4 and 8.1 Hz); 8.08 (d, 1H, 5.9 Hz); 9.03 (d, 1H, J = 5.9 Hz); 9.07 (dd, 1H , J=4.4 and 1.8Hz); 9.18 (s, 1H); 9.19 (dd, 1H, J=1.8 and 8.1Hz).

· ¹³ C NMR (CDCl ₃ ): 116.63; 119.80; 128.25; 132.64; 134.05; 137.03; 145.92; 147.56; 147.78(2C); 148.47;

· IR (chloroform): 1692; 1608 cm ^-1 .

MS: m/z 269(34); 267(100); 232(60); 204(29).

Example 17

4-Dimethylamino-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL 8807) and 4-dimethylamino-7H-pyrido[4,3 ,2-de][1,7]phenanthroline-7-one (CRL 8481)

A solution of compound CRL 8806 or compound CRL 8480 (14mg, 0.052mmol), dimethylammonium chloride (24mg, 0.29mmol) and sodium hydroxide (13mg, 0.32mmol) in THF/water (4ml/2ml) mixture Reflux for 1 hour and 30 minutes. After concentration with a rotary evaporator, 15 ml of water were added.

After extraction with chloroform (3 x 20 ml), the organic phase was dried over magnesium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by flash chromatography (95/5 chloroform/MeOH) to afford the expected compound as a red powder.

4-Dimethylamino-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRI8481)

• Yield: 63% (9 mg).

· Melting point: >260°C.

· ¹ H NMR (CDCl ₃ ): 3.34(s, 6H); 7.71 (dd, 1H, J = 4.4 and 8.1Hz); 7.96(d, 1H, 6.0Hz); 8.62(s, 1H); 8.83(d , 1H, J=6.0Hz); 9.04 (dd, 1H, J=1.5 and 4.4Hz); 9.19 (dd, 1H, J=1.5 and 8.1Hz).

· ¹³ C NMR (CDCl ₃ ): 44.06 (2C); 117.89; 120.40; 127.22; 129.69; 132.59; 133.68; 135.30;

· IR (chloroform): 1666 cm ^-1 .

· MS: m/z 276(100); 249(11); 204(1).

Example 18

3-Acetoxymethyl-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL 8825) and 3-acetoxymethyl-7H-pyrido [4,3,2-de][1,7]phenanthroline-7-one (CRL 8824)

Under a nitrogen atmosphere, a solution of compound I-1b or compound II-1b (0.11 g, 0.5 mmol) and dimethylformamide diethyl acetal (1.5 mmol) in DMF (3 ml) was heated at 120° C. 1 hour. After cooling, the mixture was concentrated in vacuo to afford the expected derivative as a solid. The solid derivative (125 mg, 0.45 mmol) was transferred into DMF and 13 mg (0.7 mmol) of Eschenmoser's salt was added. Under a nitrogen atmosphere, the mixture was heated at 115°C for 30 minutes. After cooling, ammonium chloride (10 mmol) and acetic acid (75 ml) were added to the mixture, which was left at 115°C for 30 minutes. After cooling, the reaction mixture was poured into ice, basified with 10% KOH and extracted with chloroform. The organic phase was dried over magnesium sulfate and concentrated on a rotary evaporator. The residue was purified by flash chromatography on silica gel.

Prepared as described above

3-acetal-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one (CRL 8815) and 3-acetal-7H-pyrido[4,3 , 2-de][1,7]phenanthroline-7-one (CRL 8814)

3-cyano-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL8817) and 3-cyano-7H-pyrido[4,3,2- de][1,7]phenanthrolin-7-one (CRL8816)

3-ethoxycarbonyl-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL 8819) and 3-ethoxycarbonyl-7H7-pyrido[4,3 ,2-de][1,7]phenanthroline-7-one (CRL 8818)

3-methoxymethyl-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL 882 1) and 3-methoxymethyl-7H7-pyridine And[4,3,2-de][1,7]phenanthrolin-7-one (CRL 8820)

3-fluoro-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL 8823) and 3-fluoro-7H-pyrido[4,3,2-de ][1,7]phenanthroline-7-one (CRL 8822)

3-Acetoxymethyl-9-methoxy-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL 8825) and 3-acetoxymethyl Methyl-9-methoxy-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL 8824)

Example 19

2-Methyl-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL8827) and 2-methyl-7H-pyrido[4,3,2- de][1,7]phenanthrolin-7-one (CRL8826)

A mixture of compound I-1b and compound II-b (80 mg, 0.4 mmol) was dissolved in acetic acid (10 ml) containing ammonium chloride (64 mg, 12 mmol), and the solution was heated to 70°C while maintaining stirring. Acetaldehyde (88mg, 2mmol) in acetic acid (10ml) was added dropwise. The mixture was heated to reflux for 45 minutes under a nitrogen atmosphere and then cooled. After watering, the solution was basified with _NH4OH and extracted with dichloromethane. After drying over magnesium sulfate and evaporation, the resulting residue was purified by flash chromatography on silica gel.

Prepared as described above

2-Benzyl-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL8829) and 2-benzyl-7H-pyrido[4,3,2- de][1,7]phenanthrolin-7-one (CRL8828)

2-(2'-chloroethyl)-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL 8831) and 2-(2'-chloroethyl )-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL 8830)

2-(2'-methoxymethyl)-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one (CRL 8833) and 2-(2'-methyl Oxymethyl)-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one (CRL 8832)

The results of in vitro and in vivo pharmacological tests hereinafter demonstrate the cytotoxic properties and the limiting tolerated dose (MTD) of the compounds of formula (I) and (Ia). -1- Cytotoxic activity on tumor cell lines in medium (MTT assay)

Formulas (I) and (Ia ) compounds on tumor cells.

The principle of the MTT test is based on the metabolism of the yellow product MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) to the blue product, triphenylmethyl ester Reduction of metabolically active mitochondria in living cells. The amount of trityls thus obtained is directly proportional to the amount of viable cells present in the medium wells. The amount of triphenylmethane was measured by spectrophotometry.

Cell lines were maintained in monolayer culture in stoppered dishes containing 25MM HEPES MEM (Minimum Essential Medium) basic medium at 37°C. This medium is well suited for the growth of a wide variety of diploid or primary mammalian cells. The medium is then supplemented with the following substances:

- with 5% FCS (fetal calf serum) decomplemented for 1 hour at 56°C,

- with 0.6mg/ml L-glutamine,

- with 200lU/ml penicillin,

- with 200 (J-g/ml streptomycin,

- With 0.1 mg/ml gentamicin.

The 12 human cancer cell lines used were obtained from the AmeRlcan Type Culture Collection (ATCC, Rockyille, MD, USA). The 12 cell lines are:

- two malignant gliomas U-373MG (ATCC code: HTB-17) and U-87MG (ATCC code: HTB-14),

An astrocytoma SW1088 (ATCC code: HTB-12),

- Two types of non-small cell lung cancer A549 (ATCC code: CCL-185) and A-427 (ATCC code: HTB-53),

- Two types of colon cancer HCT-15 (ATCC code: CCL-225) and LoVo (ATCC code: CCL-229),

- Two breast cancers T-47D (ATCC code: HTB-133) and MCF7 (ATCC code: HTB-22),

- Two types of bladder cancer J82 (ATCC code: HTB-1) and T24 (ATCC code: HPB-4),

- Prostate cancer, PC-3 (ATCC code: CRL-1435).

Experimental method: 100 μl of cell suspension containing 20,000 to 50,000 (depending on the cell type used) cells/ml medium was cultured in a 96-well flat-bottom multiwell plate at 37°C, including an atmosphere of 5% CO ₂ and 70% humidity. After 24 hours of incubation, the medium was replaced with 100 µl of a new medium containing each test compound at a concentration of 10 ^-5 to 10 ^-10 M or a solvent for dissolving the test product (control condition). After culturing under the above conditions for 72 hours, the medium was replaced with a light yellow solution of dissolved MTT in a ratio of 1 mg/ml in 100 μl RPMI 1640. The microplate was incubated for an additional 3 hours at 37°C and then centrifuged at 400g for 10 minutes. The pale yellow MTT solution was removed, and the blue trityl crystals formed at the cellular level were dissolved in 100 μl DMSO. The microplate was then shaken for 5 minutes. The cells still alive at the end of the experiment convert the yellow MTT product to the blue triphenylmethyl ester, by spectrophotometry using a DYNATECH IMMUNOASSAY SYSTEM type device, at the wavelength corresponding to the triphenylmethyl ester limit absorption and the background noise, respectively The 570nm and 630nm wavelengths measure the blue intensity and corresponding conversion degree. Average optical density values and standard deviation (Std. Dev.) and standard error mean (SEM) were calculated using the software on the spectrophotometer.

The growth inhibitory activity of the compounds of formula (I) and (Ia) on various tumor cell lines was measured by comparison with natural products. For example, concentration values relating to the 50% inhibitory concentration ( _IC50 ) obtained for each compound are listed in Table I below:

All compounds studied showed significant Inhibitory activity, IC ₅₀ can be between 10 ^-5 and 10 ^-9 M, depending on the tested compound and tumor cell line.

2- Limiting Drug Resistance Determination (MTD)

B6D2F1/Jico mice aged 4 to 6 weeks were used for drug resistance evaluation. The compound was administered ip in increasing doses ranging from 2.5 to 160 mg/kg. The MTD value (expressed in mg/kg) was determined by observing the survival rate of the animals within 14 days after single administration of the product under study. Simultaneously monitor the change in animal weight during this period. When the MTD value is greater than 160mg/kg, the MTD value defaults to 160mg/kg for classification.

The results of the assessed limiting drug resistance dose (MTD) are summarized in Table II below:

Table II

limiting tolerance dose compound DMT (mg/kg) CRL 8388 (Example 4) 10 CRL 8293 (Example 1) 10 CRL 8294 (Example 1) 10 CRL 8363 (Example 2) 10 CRL 8364 (Example 2) 5 CRL 8367 (Example 3) 10 CRL 8396 (Example 5) 20 CRL 8400 (Example 6) >160 CRL 8401 (Example 6) >160 CRL 8440 (Example 7) 20 CRL 8441 (Example 8) >160

Such products either have direct toxicity or lack of direct toxicity and can be used in vivo at high tissue concentrations, that is, at high doses.

3- Antitumor activity in vivo

The models tested are:

- hormone-insensitive mouse breast cancer MXT (HI-MXT),

- hormone-sensitive mouse breast cancer MXT (HI-MXT),

- Lymphoma L1210.

The mouse mammary carcinoma MXT model (Watson et al. Cancer Res., 1977; 37:3344-48) derived from mammary lactiferous ducts was transplanted into 4- to 6-week-old B6D2F1/Jico mice. Initially hormone-sensitive (HS-MXT model), differentiated tumors grow towards indifferent hormone-insensitive tumors (HI-MXT model). Agents with clinically proven to prolong antitumor activity in animal survivors were delivered to HI-MXT tumors and HS-MXT tumors.

Such agents are, for example, cyclophosphamide, etoposide or doxorubicin.

The lymphophoma L 1210 model is a model of mouse L 1210 leukemia cells derived from subcutaneous transplantation in mice. In 100% of cases, they caused rapidly growing subcutaneous solid tumors (L 1210 s.c.).

When determining the MTD value of the product, it was identified in the HS-MXT-derived mouse breast cancer model and the mouse breast cancer HI-MXT model and the subcutaneous lymphoma L 1210 model at doses of MTD/2, MTD/4 and MTD 8 In vivo antitumor activity.

In all of the following examples, regardless of the model, the control condition is that, at a rate of 3 weekly administrations (Monday, Wednesday and Friday), test 0.2ml containing the compound used to dissolve each formula (I) and (Ia ) compounds in physiological saline, administered to 9 or 15 mice for 3 consecutive weeks.

During these experiments, tumor growth or mouse survival was determined:

i) - Evaluation of tumor growth by measuring the area of transplanted HS-MXT, HI-MXT or L1210 tumors twice a week (Monday and Friday). These areas are calculated by the increase in the value of the two largest vertical axes of the tumor. Use calipers to measure the values of these axes.

II) - Calculate the survival rate of the mice as T/C form or ratio, where:

T = Median days of mice treated + (median number of mice treated - number of mice that died prior to median mice treated)/median treated mice Number of dead mice at the time of death

C = Median days of mice treated + (median number of mice treated - number of mice that died prior to median treated mice)/median Number of dead mice at the time of mouse death

The ratio represents the mean survival of treated mice relative to the median mean survival of control mice. Thus, molecular induction significantly (P<0.05) increased animal survival when the T/C index exceeded 130%. On the other hand, when the T/C value is less than 70%, it has a toxic effect.

3.1.- Mouse breast cancer (HI-MXT)

The effects of the two products CRL 8293 and CRL 8294 on the growth of HI-MXT tumors will be described below by way of examples. Each batch of mice implanted with HI-MXT tumors associated with a given experimental condition consisted of 15 animals.

processing 1

The product CRL 8293 was administered intraperitoneally.

The first injection of the product was carried out on the seventh day (D7) after the transplantation. From the seventh day (D7) after the transplantation, it was injected at a rate of 3 times a week (Monday, Wednesday and Friday) for 3 weeks, and the dose was 5mg/kg .

processing 2

The product CRL 8294 was administered intraperitoneally.

The first injection of the product was carried out on the seventh day (D7) after the transplantation. From the seventh day (D7) after the transplantation, it was injected at a rate of 3 times a week (Monday, Wednesday and Friday) for 3 weeks, and the dose was 5mg/kg .

After 21 days of tumor transplantation, that is, after 6 administrations of the product CRL 8293 or the product CRL 8294, the reduction (-) or increase (+) of the HI-MXT tumor area induced by treatment 1 and 2 relative to the control condition is shown in the following table II as a percentage middle. 21 days after transplantation, 100% of control animals were still alive.

Table III deal with Tumor area (expressed in %) 1 (CRL 8293) -33 2 (CRL 8294) -36

These results show that the two products, CRL 8293 and CRL 8294, induce a significant reduction in HI-MXT tumor growth. These results show that the products of Formula I and Ia have beneficial antitumor activity both in vivo and in this model.

3.2.- Mouse breast cancer (HS-MXT)

The effects of the two products CRL 8293 and CRL 8294 on the growth of HS-MXT tumors will be described below by way of examples. Each batch of mice implanted with HS-MXT tumors associated with a given experimental condition consisted of 9 animals.

Process 10

The product CRL 8293 was administered intraperitoneally.

The first injection of the product was carried out on the seventh day (D7) after the transplantation. From the seventh day (D7) after the transplantation, it was injected at a rate of 3 times a week (Monday, Wednesday and Friday) for 3 weeks, and the dose was 5mg/kg .

Process 20

The product CRL 8294 was administered by the intraperitoneal route alone. The first injection of the product was carried out on the seventh day (D7) after the transplantation. From the seventh day (D7) after the transplantation, it was injected at a rate of 3 times a week (Monday, Wednesday and Friday) for 3 weeks, and the dose was 5mg/kg .

Tumor transplantation 31 days, namely after product CRL 8293 or product CRL 8294 9 administrations, relative to the control condition treatment 10 and 20 induced reduction (-) or increase (+) of HS-MXT tumor area is shown in the following table IV in percentage middle. 31 days after transplantation, 100% of control animals were still alive.

Table IV deal with Tumor area (expressed in %) 10 (CRL 8293) -45 20 (CRL 8294) -64

These results show that the two products, CRL 8293 and CRL 8294, induced a very significant reduction in HS-MXT tumor growth. Like the HI-MXT model, these results show that the products of formula I and Ia also have high beneficial antitumor activity against HS-MXT.

3.3.- Lymphoma L 1210.

The impact of CRL 8294 mouse survival time will be described below in the form of examples (Table V). Each batch of mice implanted with HS-MXT tumors associated with a given experimental condition consisted of 9 animals.

Process 100

The product CRL 8294 was administered alone intraperitoneally. The first injection of the product was carried out on the seventh day (D7) after the transplantation, and the rate of 3 times a week (Monday, Wednesday and Friday) was continuously injected for 3 weeks from the seventh day (D7) after the transplantation, and the dose was 1.25mg/ kg.

Table V deal with T/C (expressed in %) 100 (CRL 8294) -136

Formula (I) compound CRL 8294 shows antitumor activity to subcutaneous lymphoma L 1210 model. This activity is characterized by a significant increase in the median mouse survival of the treated mice compared to the median mouse survival of the control mice.

4- Tolerance/cytotoxic activity ratio

Mean _IC50 values (in nM) (calculated from individual cytotoxic activities obtained from studies on 12 tumor cell lines) and MTD/ _IC50 ratios, obtained by the ratio of MTD values to _IC50 values, are presented in Table VI below . The MTD/ _IC50 ratio is expressed as a dimensionless number.

Table VI compound IC ₅₀ (nM) MTD/IC ₅₀ MTD/ _IC50 ^* CRL 8388 (Example 4) 6200 0.0016 1 CRL 8293 (Example 1) 1250 0.008 5 CRL 8294 (Example 1) 1450 0.007 4.4 CRL 8363 (Example 2) 500 0.02 12.5 CRL 8364 (Example 2) 270 0.019 12 CRL 8367 (Example 3) 1650 0.006 3.8 CRL 8396 (Example 5) 600 0.033 20.6 CRL 8400 (Example 6) 380 0.42 262 CRL 8401 (Example 6) 53 3 1870 CRL 8440 (Example 7) 10 0.42 1240 CRL 8441 (Example 8) 5000 3 19.8

*: The MTD/IC50 ratios of the various compounds were obtained by taking the ratio equal to 1 for CRL 8388 as a reference.

Under the experimental conditions described above, the compounds of formula (I) and (Ia) exhibited significant in vitro and in vivo antitumor activity.

The results of MTT colorimetric assay showed that they inhibited the growth of tumor cells in vitro. In vivo, they significantly and greatly inhibited the growth of HI-MXT and HS-MXT tumors, significantly increased the median survival time of mice treated and transplanted with lymphoma L 1210 compared to control group mice Median of mice Average survival time of mice.

On the basis of their cytotoxic properties, the compounds of formula (I) and (Ia) disclosed above, or their pharmaceutically acceptable salts or solvates, can be used as active ingredients of medicaments for the treatment of cancerous tumors and their metastases.

The compounds of formula (I) and (Ia) are generally administered in dosage units formulated per ^m2 of body surface area or per kg of body weight. The above dosage units are preferably formulated in pharmaceutical compositions, wherein the active ingredient is in admixture with one (or more) pharmaceutical excipients.

The dosage of the compound of formula (I) and (Ia) used is between 0.05 and 350 mg/m ² body surface area according to the cancer condition of the patient being treated, and the preferred dosage is 0.5 to 50 mg/m ² during acute phase drug therapy /day, related to the number of treatment cycles. The dose of the compound of formula (I) and (Ia) used in maintenance therapy is 0.05 to 25 mg/m ² /day, preferably 0.1 to 1.5 mg/m ² /day, depending on the number of treatment cycles. They can be used in combination with antineoplastic drugs for enhanced comprehensive chemotherapy effective courses.

In the pharmaceutical composition of the present invention for oral or intravenous administration, the active ingredient may be administered in a unit dosage form, such as admixture with conventional formulation excipients suitable for human therapeutics. Suitable unit dosage forms include oral administration forms such as tablets, optionally scored, or capsules, implants and intravenous administration forms.

Formulations for parenteral administration (injection into a vein at a constant flow rate) include sterile aqueous suspensions, sterile isotonic saline solutions or sterile and injectable solutions containing pharmacologically compatible dispersing agents and/or boosters. Solvents such as propylene glycol, polyethylene glycol or R-cyclodextrin.

Therefore, co-solvents are used when preparing aqueous solutions for intravenous injection designed for 1 to 24 hour infusion: alcohols, such as ethanol, or glycols, such as polyethylene glycol or propylene glycol, and hydrophilic surfactants, such as Tween 80.

When preparing a solid composition in the form of tablets, wetting agents, sodium lauryl sulfate, can be added to micronized or non-micronized active ingredients, and after complete combination with pharmaceutical carriers, such as silica gel, gelatin, starch, lactose, Magnesium stearate, talc, gum arabic, etc. are blended. Tablets may be coated with sucrose, various polymers or other suitable materials and when they are selectively processed they have sustained or delayed properties so that they continuously release a predetermined amount of the active ingredient.

Capsule preparations are obtained by mixing the active ingredient with a diluent such as glycol or glyceride, and filling the resulting mixture into soft or hard capsules.

The active ingredients can also be optionally formulated into microcapsules or microspheres with one or more carriers or additives.

The active ingredient can also form complexes with cyclodextrins, for example α-, β- or γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin.

Due to their potent cytotoxic activity, the compounds of formula (I) and (Ia) are useful in the treatment of most solid tumors, especially in the treatment of brain tumors, lung cancer, ovarian and breast tumors, endometrial cancer, colon cancer, prostate cancer and testicular tumors.

Claims (15)

1. Compounds of general formula I or Ia or the addition salts of these compounds and pharmaceutically acceptable acids: Formula I and Formula Ia in: R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are selected from hydrogen, halogen, C ₁ -C ₆ alkyl, hydroxyl, -CHO, -OR ₈ , -COOH, -CN, -CO ₂ R ₈ , - CONHR ₈ , -CONR ₈ R ₉ , -NH ₂ , -NHR ₈ , N(R ₈ ) ₂ , -NH-CH ₂ -CH ₂ -N(CH ₃ ) ₂ , -NH-CH ₂ -CH ₂ -Cl , -NHCOR ₈ , morpholino, nitro, SO ₃ H, R ₈ and R ₉ are selected from C ₁ -C ₆ alkyl and phenyl(C ₁ -C ₄ )alkyl and Ar is C ₆ -C ₁₄ aryl, -R ₆ is selected from hydrogen, halogen, C ₁ -C ₆ alkyl or wherein R ₁₀ is selected from halogen or -OH, (C ₁ -C ₆ )alkoxy or -O-CO-(C ₁ -C ₆ ) Alkyl with n between 1 and 6 -(CH ₂ ) _n R ₁₀ group, -CN, -CO ₂ Et or wherein R ₁₁ is selected from C ₁ -C ₆ alkyl and phenyl (C ₁ -C ₄ ) A -COR ₁₁ group of an alkyl group having wherein R ₁₂ and R ₁₃ are independently selected from hydrogen or C ₁ -C ₆ alkyl, phenyl(C ₁ -C ₄ )alkyl or -(CH ₂ ) NR ₁₂ R ₁₃ of _n R ₁₄ groups, -wherein R ₁₄ is selected from halogen, (C ₁ -C ₆ )alkoxy and N(CH ₃ ) ₂ groups and n is between 1 and 6, -R ₇ is selected from hydrogen, (C ₁ -C ₆ ) alkyl, phenyl (C ₁ -C ₄ ) alkyl, wherein R ₁₅ and R ₁₆ are independently selected from hydrogen, C ₁ -C ₆ alkyl and NR ₁₅ R _{16 of} phenyl ₍ C ₁ -C ₄ )alkyl and ( _{CH 2} ) _n R ₁₇ group. 2. The compound of claim 1, wherein _R6 = _R7 =H. 3. The compound of formula I and/or la according to claim 1 or 2, wherein: R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are selected from hydrogen, halogen, C ₁ -C ₆ alkyl, hydroxyl, -CHO, -OR ₈ , -COOH, -CN, -CO ₂ R ₈ , - CONHR ₈ , -CONR ₈ R ₉ , -NH ₂ , -NHR ₈ , N(R ₈ ) ₂ , -NH-CH ₂ -CH ₂ -N(CH ₃ ) ₂ , -NHCOR ₈ , morpholino, nitrate base, SO ₃ H,

R ₈ and R ₉ are selected from C ₁ -C ₆ alkyl and Ar is C ₆ -C ₁₄ aryl. 4. The compound of formula I and formula Ia or a pharmaceutically acceptable acid addition salt thereof according to claim 1, wherein: R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are selected from hydrogen, halogen, C ₁ -C ₆ alkyl, hydroxyl, -OR ₈ , -NO ₂ , -NH ₂ , -NHR ₈ , -N(R ₈ ) ₂ , -NH-CH ₂ -CH ₂ -N(CH ₃ ) ₂ , -NH-CH ₂ -CH ₂ -Cl, NHCOR ₈ , R ₈ is selected from C ₁ -C ₆ alkyl, -R ₆ is selected from hydrogen, wherein R ₁₀ is selected from halogen, -(CH ₂ ) _n R ₁₀ groups of -O-CO-CH ₃ and wherein R ₁₂ and R ₁₃ are independently selected from hydrogen, C ₁ -C ₆ N(R ₁₂ R ₁₃ ) groups of alkyl, benzyl or -(CH ₂ ) _n R ₁₄ groups, wherein R ₁₄ is selected from halogen or (C ₁ -C ₆ )alkoxy and N(CH ₃ ) ₂ groups with n between 1 and 6, -R ₇ is selected from hydrogen, (C ₁ -C ₆ ) alkyl, benzyl, wherein R ₁₅ and R ₁₆ are selected from hydrogen, C ₁ -C ₆ alkyl and benzyl N(R ₁₅ R ₁₆ ) groups and (CH ₂ ) _n R ₁₇ groups wherein R ₁₇ is selected from hydrogen, halogen or OH or (C ₁ -C ₆ )alkoxy and n is between 1 and 6. 5. The compound according to claim 4, wherein at least one R ₁ , R ₂ , R ₃ , R ₄ or R ₅ in the compound of formula I or Ia is an OR ₈ group. 6. The compound according to claim 4, wherein the compound of formula I and/or Ia is a compound wherein the radicals are defined as follows or an addition salt of these compounds with a pharmaceutically acceptable acid: R ₁ is selected from hydrogen, halogen or hydroxyl, methoxy, nitro, -NH ₂ , -NHCH ₃ , -NH-CH ₂ -CH ₂ -N(CH ₃ ) ₂ , -NH-CH ₂ -CH ₂ - Cl or _NHCOCH3 group, _R2 is hydrogen, _R3 and _R5 are selected from hydrogen or hydroxy or methoxy. 7. The compound according to claim 4, wherein the compound of formula I is the following compound or an addition salt of these compounds with a pharmaceutically acceptable acid: 11-methoxy-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one, 11-chloro-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one, 4-methoxy-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one, 4,11-dimethoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one, 4,9-dimethoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one, 9-methoxy-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one, 9,11-dimethoxy-7H-pyrido[4,3,2-de][1,7]phenanthroline-7-one, 3-Acetoxymethyl-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one, 3-Acetoxymethyl-9-methoxy-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one, 2-(2-Chloroethyl)-7H-pyrido[4,3,2-de][1,7]phenanthrolin-7-one. 8. The compound according to claim 4, wherein the compound of formula Ia is the following compounds or the addition salts of these compounds with pharmaceutically acceptable acids: 8-methoxy-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one, 8-Chloro-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one, 4-methoxy-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one, 4,8-dimethoxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one, 4,10-dimethoxy-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one, 10-methoxy-7H-pyrido[4,3,2-de][1,10]phenanthroline-7-one, 8,10-dimethoxy-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one, 3-Acetoxymethyl-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one, 3-Acetoxymethyl-9-methoxy-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one, 2-(2-Chloroethyl)-7H-pyrido[4,3,2-de][1,10]phenanthrolin-7-one. 9. A pharmaceutical composition comprising an effective amount of a compound selected from any one of claims 1 to 8 for the treatment of cancerous tumors and their metastases. 10. Use of a compound according to any one of claims 1 to 8 for the manufacture of an anticancer drug. 11. The use according to claim 10, for the manufacture of a medicament for the treatment of solid tumors. 12. Use according to claim 11 for the manufacture of a medicament for the treatment of brain tumors, lung cancer, ovarian and breast tumors, endometrial cancer, colon cancer, prostate cancer or testicular tumors. 13. A process for preparing the compound of claim 1, comprising: a) According to the endiers-Alder reaction, by the following formula quinoline dione:

and azidodiene of the formula: where X= _CH3 reacts to give a mixture of the following compounds Formula II Formula IIa b) selectively isolating compounds of formula II and IIa, _c1 ) Subsequent reaction of compounds of formula II and/or IIa with dimethylformamide dimethyl acetal gives enamines of formula:

Formula III and / or Formula IIIa The enamine is then functionalized, introducing R _and /or R _substituents , and cyclized to give compounds I and/or Ia, or c ₂ ) while functionalizing and cyclizing, a compound of formula I and/or Ia is obtained, d) selectively isolating a compound of formula I or Ia. 14. A process for preparing wherein R _{and R} are hydrogen compounds of formula I or Ia according to claim 1, comprising: a) According to the endiers-Alder reaction, by the following formula quinoline dione:

and azidodiene of the formula: where X = CH ₂ -CH ₂ -NHBoc, react to give a mixture of the following compounds

Formula II Formula IIa b) selectively isolating compounds of formula II and IIa, c) cyclization of compounds of formula II and/or IIa to obtain compounds of formula I and/or Ia, d) selectively isolating a compound of formula I or Ia. 15. Enamines of the formula

Formula III and / or Formula IIIa wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are selected from hydrogen, halogen, C ₁ -C ₆ alkyl, hydroxyl, -CHO, -OR ₈ , -COOH, -CN, -CO ₂ R ₈ , -CONHR ₈ , -CONR ₈ R ₉ , -NH ₂ , -NHR ₈ , N(R ₈ ) ₂ , -NH-CH ₂ -CH ₂ -N(CH ₃ ) ₂ , -NH-CH ₂ -CH ₂ - Cl, -NHCOR ₈ , morpholino, nitro, SO ₃ H,

R ₈ and R ₉ are selected from C ₁ -C ₆ alkyl or phenyl(C ₁ -C ₄ )alkyl and Ar is C ₆ -C ₁₄ aryl.